Somatastatin modulators and uses thereof

ABSTRACT

Described herein are compounds that are somatostatin modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of somatostatin activity.

CROSS-REFERENCE

This application claims benefit of U.S. Provisional Patent ApplicationNo. 62/536,814 filed on Jul. 25, 2017, which is incorporated herein byreference in its entirety.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

This invention was made with the support of the United States governmentunder SBIR Grant No. 1R43DK088501-01A1, 1R44NS092231-01,2R44DK088501-02A1, and 1R43EY024185-01 by the National Institutes ofHealth.

FIELD OF THE INVENTION

Described herein are compounds that are somatostatin modulators, methodsof making such compounds, pharmaceutical compositions and medicamentscomprising such compounds, and methods of using such compounds in thetreatment of conditions, diseases, or disorders that would benefit frommodulating somatostatin activity.

BACKGROUND OF THE INVENTION

Somatostatin is a peptide hormone that regulates the endocrine systemand affects neurotransmission and cell proliferation via interactionwith G-protein-coupled somatostatin receptors and inhibition of therelease of numerous secondary hormones. Six subtype somatostatinreceptor proteins have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3,SSTR4, SSTR5) and are encoded by five different somatostatin receptorgenes. Modulation of a particular subtype somatostatin receptor, orcombination thereof, is attractive for the treatment of conditions,diseases, or disorders that would benefit from modulating somatostatinactivity.

SUMMARY OF THE INVENTION

Compounds described herein are somatostatin modulator compounds. In someembodiments, compounds described herein modulate one or more of thesubtype somatostatin receptor proteins. In some embodiments, compoundsdescribed herein modulate two or more of the subtype somatostatinreceptor proteins. Somatostatin peptide analogs, such as octreotide andpasireotide, formulated as depot injections, are routinely used tonormalize hormone levels for the treatment of GH secreting adenomas,pancreatic neuroendocrine tumors, and carcinoid tumors. Unfortunately,these analogs are only effective in about half of acromegalic patientswith GH adenomas, and patients with carcinoid tumors frequently becomeresistant to therapy due to internalization and desensitization of theSST2A receptor. In addition, these peptide drugs are extremely expensiveand require frequent doctor's office visits for painful injections thatcan lead to injection site reactions. Compounds described herein aremolecules that are structurally different from peptide analogs. Thecompounds described herein are somatostatin modulators that are potentinhibitors of hormone secretion.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,diastereomeric mixture, enantiomer or prodrug thereof:

-   -   wherein:    -   R¹ and R² are taken together with the carbon atom to which they        are attached to form —C(═O)—;    -   or R¹ and R² are each independently selected from the group        consisting of hydrogen, and unsubstituted or substituted        C₁-C₆alkyl;    -   R^(A) is hydrogen, halogen, unsubstituted or substituted        C₁-C₆alkyl, unsubstituted or substituted C₂-C₆alkenyl,        unsubstituted or substituted C₂-C₆alkynyl, unsubstituted or        substituted C₁-C₆heteroalkyl, unsubstituted or substituted        monocyclic carbocycle, unsubstituted or substituted bicyclic        carbocycle, unsubstituted or substituted monocyclic heterocycle,        or unsubstituted or substituted bicyclic heterocycle, wherein if        R^(A) is substituted then R^(A) is substituted with 1-2 R¹⁰ and        0-2 R¹¹;    -   R^(B) is unsubstituted or substituted C₁-C₆alkyl, unsubstituted        or substituted C₂-C₆alkenyl, unsubstituted or substituted        C₂-C₆alkynyl, unsubstituted or substituted C₁-C₆heteroalkyl,        unsubstituted or substituted monocyclic carbocycle,        unsubstituted or substituted bicyclic carbocycle, unsubstituted        or substituted monocyclic heterocycle, unsubstituted or        substituted bicyclic heterocycle, wherein if R^(B) is        substituted then R^(B) is substituted with 1-2 R¹² and 0-2 R¹³;    -   A¹, A², and A³ are independently CR^(C) or N;        -   each R^(C) is independently hydrogen, halogen, unsubstituted            or substituted C₁-C₄alkyl, unsubstituted or substituted            C₁-C₄fluoroalkyl, unsubstituted or substituted C₁-C₄alkoxy,            unsubstituted or substituted C₁-C₄fluoroalkoxy, —CN, —OH,            —CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —NR¹⁴C(═O)R¹⁵, —SR¹⁴,            —S(═O)R¹⁵, —SO₂R¹⁵, or —SO₂NR¹⁴R¹⁵;    -   R³ and R⁴ are independently hydrogen, unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted        C₁-C₆fluoroalkyl, or unsubstituted or substituted        C₃-C₆cycloalkyl, wherein any substituted group of R³ and R⁴ is        substituted with 1-4 R¹⁶;    -   or R³ and R⁴ are taken together with the nitrogen atom to which        they are attached to form an unsubstituted or substituted        monocyclic or bicyclic heterocyclic ring, wherein if the        heterocyclic ring is substituted then the heterocyclic ring is        substituted with 1-4 R¹⁶;    -   R⁵, R⁶, R⁷, and R⁸ are each independently selected from the        group consisting of hydrogen, unsubstituted or substituted C₁-C₆        alkyl, and unsubstituted or substituted C₁-C₆fluoroalkyl,        unsubstituted or substituted monocyclic carbocycle,        unsubstituted or substituted monocyclic heterocycle, wherein any        substituted group of R⁵, R⁶, R⁷, and R⁸ is substituted with 1-4        R¹⁶;    -   R⁹ is hydrogen, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or unsubstituted or substituted benzyl, wherein if        R⁹ is substituted then R⁹ is substituted with 1-4 R¹⁶;    -   or R⁴ and any one of R⁵, R⁷, or R⁹ are taken together with the        intervening atoms to which they are attached to form an        unsubstituted or substituted monocyclic 4- to 7-membered        heterocyclic ring or an unsubstituted or substituted bicyclic 9-        to 12-membered heterocyclic ring, wherein if the heterocyclic        ring is substituted then the heterocyclic ring is substituted        with 1-4 R¹⁶;    -   or R⁵ and any one of R⁶, R⁷ or R⁹ are taken together with the        intervening atoms to which they are attached to form an        unsubstituted or substituted monocyclic 4- to 7-membered ring or        a bicyclic 9- to 12-membered ring, wherein if the heterocyclic        ring is substituted then the heterocyclic ring is substituted        with 1-4 R¹⁶;    -   or R⁷ and R⁹ are taken together with the intervening atoms to        which they are attached to form an unsubstituted or substituted        monocyclic 4- to 7-membered heterocyclic ring or an        unsubstituted or substituted bicyclic 9- to 12-membered        heterocyclic ring, wherein if the heterocyclic ring is        substituted then the heterocyclic ring is substituted with 1-4        R¹⁶;    -   each R¹⁰, R¹¹, R¹² and R¹³ is independently hydrogen, halogen,        unsubstituted or substituted C₁-C₄alkyl, unsubstituted or        substituted C₁-C₄alkoxy, unsubstituted or substituted        C₁-C₄fluoroalkyl, unsubstituted or substituted        C₁-C₄fluoroalkoxy, unsubstituted or substituted monocyclic        carbocycle, unsubstituted or substituted monocyclic heterocycle,        —CN, —OH, —CO₂R¹⁴, —CH₂CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵, —CH₂C(═O)NR¹⁴R¹⁵,        —NR¹⁴R¹⁵, —CH₂NR¹⁴R¹⁵, —NR¹⁴C(═O)R¹⁵, —CH₂NR¹⁴C(═O)R¹⁵, —SR¹⁴,        —S(═O)R¹⁵, —SO₂R¹⁵, or —SO₂NR¹⁴R¹⁵, wherein if any group of R¹⁰,        R¹¹, R¹² and R¹³ is substituted then the substituted group of        R¹⁰, R¹¹, R¹² and R¹³ is substituted with 1-4 R¹⁶;    -   each R¹⁶ is independently halogen, C₁-C₆alkyl, heterocycle, —CN,        —OR¹⁴, —CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —NR¹⁴C(═O)R¹⁵, —SR¹⁴,        —S(═O)R¹⁵, —SO₂R¹⁵, or —SO₂NR¹⁴R¹⁵;    -   each R¹⁴ is independently selected from H, unsubstituted or        substituted C₁-C₆alkyl, unsubstituted or substituted        C₁-C₆heteroalkyl, substituted or unsubstituted unsubstituted or        substituted C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl;    -   each R¹⁵ is independently selected from H, unsubstituted or        substituted C₁-C₆alkyl, unsubstituted or substituted        C₁-C₆heteroalkyl, substituted or unsubstituted unsubstituted or        substituted C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl; or R¹⁴ and R¹⁵ are        taken together with the N atom to which they are attached to a        substituted or unsubstituted N-containing heterocycle;    -   m is 1, 2, 3, or 4.

Also described herein is a pharmaceutical composition comprising acompound described herein, or a pharmaceutically acceptable salt, orsolvate thereof, and at least one pharmaceutically acceptable excipient.In some embodiments, the pharmaceutical composition is formulated foradministration to a mammal by intravenous administration, subcutaneousadministration, oral administration, inhalation, nasal administration,dermal administration, or ophthalmic administration. In someembodiments, the pharmaceutical composition is formulated foradministration to a mammal by oral administration. In some embodiments,the pharmaceutical composition is in the form of a tablet, a pill, acapsule, a liquid, a suspension, a gel, a dispersion, a solution, anemulsion, an ointment, or a lotion. In some embodiments, thepharmaceutical composition is in the form of a tablet, a pill, or acapsule.

Also described herein is a method of treating a disease or condition ina mammal that would benefit from the modulation of somatostatin receptoractivity comprising administering a small molecule non-peptidylcompound, or pharmaceutically acceptable salt, or solvate thereof, tothe mammal in need thereof. In some embodiments, the small moleculenon-peptidyl compound is orally administered. In some embodiments, thesmall molecule non-peptidyl compound is a compound as described herein,or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, the small molecule non-peptidyl compound is a SSTR2modulator as described herein, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the disease or condition isacromegaly, a neuroendocrine tumor, an ophthalmic disease or condition,neuropathy, nephropathy, a respiratory disease or condition, cancer,pain, a neurodegenerative disease or condition, an inflammatory diseaseor condition, a psychiatric disease or condition, or combinationsthereof.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound of Formula (I), or apharmaceutically acceptable salt thereof, is: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by inhalation; and/or (e) administered by nasaladministration; or and/or (f) administered by injection to the mammal;and/or (g) administered topically to the mammal; and/or (h) administeredby ophthalmic administration; and/or (i) administered rectally to themammal; and/or (j) adminstered non-systemically or locally to themammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which the compound is administered oncea day to the mammal or the compound is administered to the mammalmultiple times over the span of one day. In some embodiments, thecompound is administered on a continuous dosing schedule. In someembodiments, the compound is administered on a continuous daily dosingschedule.

In any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, compounds provided herein are orally administeredto a human.

Articles of manufacture, which include packaging material, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, within thepackaging material, and a label that indicates that the compound orcomposition, or pharmaceutically acceptable salt, tautomers,pharmaceutically acceptable N-oxide, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, is used for modulating one or more subtype somatostatinreceptor proteins, or for the treatment, prevention or amelioration ofone or more symptoms of a disease or condition that would benefit frommodulating one or more subtype somatostatin receptor proteins, areprovided.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Somatostatin (SST), also known as somatotropin release inhibiting factor(SRIF) was initially isolated as a 14-amino acid peptide from ovinehypothalamii (Brazeau et al., Science 179, 77-79, 1973). An N-terminalextended 28-amino acid peptide with similar biological activity to14-amino acid somatostatin was subsequently isolated (Pradayrol et, al.,FEBS Letters, 109, 55-58, 1980; Esch et al., Proc. Natl. Acad. Sci. USA,77, 6827-6831, 1980). SST is a regulatory peptide produced by severalcell types in response to other neuropeptides, neurotransmitters,hormones, cytokines, and growth factors. SST acts through both endocrineand paracrine pathways to affect its target cells. Many of these effectsare related to the inhibition of secretion of other hormones, mostnotably growth hormone (GH). They are produced by a wide variety of celltypes in the central nervous sstem (CNS) and gut and have multiplefunctions including modulation of secretion of growth hormone (GH),insulin, glucagon, as well as many other hormones that areanti-proliferative.

These pleotropic actions of somatostatins are mediated by sixsomatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4,SSTR5). The six somatostatin receptor proteins are encoded by fivedifferent somatostatin receptor genes (Reisine and Bell, Endocr Rev. 16,427-442, 1995; Patel and Srikant, Trends Endocrinol Metab 8, 398-405,1997). All the receptors are members of the class-A subgroup of the GPCRsuperfamily. SST2A receptor is the most widely expressed subtype inhuman tumors and is the dominant receptor by which GH secretion issuppressed.

It is possible to selectively modulate any one of the somatostatinreceptor subtypes, or combination thereof. In some embodiments,selectively modulating any one of the somatostatin receptor subtypesrelative to the other somatostatin receptor subtypes, or combinationthereof, in useful in a variety of clinical applications.

For example, modulation of SSTR2 activity mediates the inhibition ofgrowth hormone (GH) release from the anterior pituitary and glucagonrelease from pancreas. SSTR2 is also implicated in many other biologicalfunctions such as, but not limited to, cell proliferation, nociception,inflammation, and angiogenesis. In some embodiments, a selective SSTR2modulator is used in the treatment of acromegaly, gut neuroendocrinetumors, pain, neuropathies, nephropathies, and inflammation, as well asretinopathies resulting from aberrant blood vessel growth. In some otherembodiments, a selective SSTR2 modulator is used in the treatment ofarthritis, pain, cancer, inflammatory bowel disease, irritable bowelsyndrome, Crohn's disease, Cushing's disease, acute lung injury, acuterespiratory distress syndrome, and ophthalmic disorders such asage-related macular degeneration (AMD), diabetic retinopathy, diabeticmacular edema, and Graves ophthalmology, among others.

In some embodiments, SSTR4 agonists exhibit anti-inflammatory andanti-nociceptive effects.

In some embodiments, SSTR3 agonists inhibit insulin secretion.

In some embodiments, SSTR5 agonists inhibit insulin secretion. Inaddition, SSTR5 has also been implicated to modulate the release ofgrowth hormone.

Somatostatin peptide and its receptor subtypes are also widely expressedin the brain and disruption or diminishment of their activity ispotentially involved in several psychiatric and neurodegenerativediseases. For example, concentrations of somatostatin in the cerebralcortex and hippocampus are reduced in schizophrenics and one of the mostconsistent neuropathologic findings in this patient group is a deficitin cortical inhibitory interneurons expressing somatostatin.Somatostatin is also highly expressed in brain regions associated withseizures and has also been implicated as having an important role inepilepsy. Somatostatin levels are diminished in the hippocampi ofAlzheimer's and Parkinson's patients, suggesting that restoration of itssignaling as a potential drug target for neurodegeneration.

In one aspect, compounds described herein are modulators of SSTR2. Insome embodiments, compounds described herein selectively modulate theactivity of SSTR2 relative to the other somatostatin receptors.

In some embodiments, compounds described here are amenable to oraladministration to a mammal in need of treatment with a somatostatinmodulator.

In some embodiments, somatostatin receptor modulators described hereinhave utility over a wide range of therapeutic applications. In someembodiments, somatostatin receptor modulators described herein are usedin the treatment of a variety of diseases or conditions such as, but notlimited to acromegaly, neuroendocrine tumors, retinopathies and otherophthalmic disorders, neuropathy, nephropathy, respiratory diseases,cancers, pain, neurodegenerative diseases, inflammatory diseases, aswell as psychiatric and neurodegenerative disorders. In someembodiments, somatostatin receptor modulators described herein are usedin the treatment of acromegaly in a mammal.

In some embodiments, somatostatin receptor modulators described hereininhibit the secretion of various hormones and trophic factors inmammals. In some embodiments, the compounds are used to suppress certainendocrine secretions, such as, but not limited to GH, insulin, glucagonand prolactin. The suppression of certain endocrine secretions is usefulin the treatment of disorders such as acromegaly; endocrine tumors suchas carcinoids, VIPomas, insulinomas and glucagonomas; or diabetes anddiabetes-related pathologies, including retinopathy, neuropathy andnephropathy. In some embodiments, somatostatin receptor modulatorsdescribed herein are used to suppress exocrine secretions in thepancreas, stomach and intestines, for the treatment of disorders such aspancreatitis, fistulas, bleeding ulcers and diarrhea associated withsuch diseases as AIDS or cholera. Disorders involving autocrine orparacrine secretions of trophic factors such as IGF-1 (as well as someendocrine factors) which may be treated by administration of thecompounds described herein include cancers of the breast, prostate, andlung (both small cell and non-small cell epidermoids), as well ashepatomas, neuroblastomas, colon and pancreatic adenocarcinomas (ductaltype), chondrosarcomas, and melanomas, diabetic retinopathy, andatherosclerosis associated with vascular grafts and restenosis followingangioplasty.

In some embodiments, somatostatin receptor modulators described hereinare used to suppress the mediators of neurogenic inflammation (e.g.substance P or the tachykinins), and may be used in the treatment ofrheumatoid arthritis; psoriasis; topical inflammation such as isassociated with sunburn, eczema, or other sources of itching;inflammatory bowel disease; irritable bowel syndrome; allergies,including asthma and other respiratory diseases In some otherembodiments, the somatostatin receptor modulators described hereinfunction as neuromodulators in the central nervous system and are usefulin the treatment of Alzheimer's disease and other forms of dementia,pain, and headaches. In some embodiments, somatostatin receptormodulators described herein provide cytoprotection in disordersinvolving the splanchnic blood flow, including cirrhosis and oesophagalvarices.

Compounds

Compounds of Formula (I), including pharmaceutically acceptable salts,prodrugs, active metabolites and pharmaceutically acceptable solvatesthereof, are somatostatin receptor modulators. In some embodiments, thecompounds of Formula (I), including pharmaceutically acceptable salts,prodrugs, active metabolites and pharmaceutically acceptable solvatesthereof, are SSTR2 receptor modulators. In some embodiments, thesomatostatin receptor modulators are somatostatin receptor agonists.

In one aspect, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,diastereomeric mixture, individual enantiomers or prodrug thereof:

Provided in one aspect is a compound that has the structure of Formula(I), or a pharmaceutically acceptable salt, solvate, diastereomericmixture, individual enantiomers or prodrug thereof:

-   -   wherein:    -   R¹ and R² are taken together with the carbon atom to which they        are attached to form —C(═O)—;    -   or R¹ and R² are each independently selected from the group        consisting of hydrogen, and unsubstituted or substituted        C₁-C₆alkyl;    -   R^(A) is hydrogen, halogen, unsubstituted or substituted        C₁-C₆alkyl, unsubstituted or substituted C₂-C₆alkenyl,        unsubstituted or substituted C₂-C₆alkynyl, unsubstituted or        substituted C₁-C₆heteroalkyl, unsubstituted or substituted        monocyclic carbocycle, unsubstituted or substituted bicyclic        carbocycle, unsubstituted or substituted monocyclic heterocycle,        or unsubstituted or substituted bicyclic heterocycle, wherein if        R^(A) is substituted then R^(A) is substituted with 1-2 R¹⁰ and        0-2 R¹¹;    -   R^(B) is unsubstituted or substituted C₁-C₆alkyl, unsubstituted        or substituted C₂-C₆alkenyl, unsubstituted or substituted        C₂-C₆alkynyl, unsubstituted or substituted C₁-C₆heteroalkyl,        unsubstituted or substituted monocyclic carbocycle,        unsubstituted or substituted bicyclic carbocycle, unsubstituted        or substituted monocyclic heterocycle, unsubstituted or        substituted bicyclic heterocycle, wherein if R^(B) is        substituted then R^(B) is substituted with 1-2 R¹² and 0-2 R¹³;    -   A¹, A², and A³ are independently CR^(C) or N;        -   each R^(C) is independently hydrogen, halogen, unsubstituted            or substituted C₁-C₄alkyl, unsubstituted or substituted            C₁-C₄fluoroalkyl, unsubstituted or substituted C₁-C₄alkoxy,            unsubstituted or substituted C₁-C₄fluoroalkoxy, —CN, —OH,            —CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —NR¹⁴C(═O)R¹⁵, —SR¹⁴,            —S(═O)R¹⁵, —SO₂R¹⁵, or —SO₂NR¹⁴R¹⁵;    -   R³ and R⁴ are independently hydrogen, unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted        C₁-C₆fluoroalkyl, or unsubstituted or substituted        C₃-C₆cycloalkyl, wherein any substituted group of R³ and R⁴ is        substituted with 1-4 R¹⁶;    -   or R³ and R⁴ are taken together with the nitrogen atom to which        they are attached to form an unsubstituted or substituted        monocyclic or bicyclic heterocyclic ring, wherein if the        heterocyclic ring is substituted then the heterocyclic ring is        substituted with 1-4 R¹⁶;    -   R⁵, R⁶, R⁷, and R⁸ are each independently selected from the        group consisting of hydrogen, unsubstituted or substituted C₁-C₆        alkyl, and unsubstituted or substituted C₁-C₆fluoroalkyl,        unsubstituted or substituted monocyclic carbocycle,        unsubstituted or substituted monocyclic heterocycle, wherein any        substituted group of R⁵, R⁶, R⁷, and R⁸ is substituted with 1-4        R¹⁶;    -   R⁹ is hydrogen, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or unsubstituted or substituted benzyl, wherein if        R⁹ is substituted then R⁹ is substituted with 1-4 R¹⁶;    -   or R⁴ and any one of R⁵, R⁷, or R⁹ are taken together with the        intervening atoms to which they are attached to form an        unsubstituted or substituted monocyclic 4- to 7-membered        heterocyclic ring or an unsubstituted or substituted bicyclic 9-        to 12-membered heterocyclic ring, wherein if the heterocyclic        ring is substituted then the heterocyclic ring is substituted        with 1-4 R¹⁶;    -   or R⁵ and any one of R⁶, R⁷ or R⁹ are taken together with the        intervening atoms to which they are attached to form an        unsubstituted or substituted monocyclic 4- to 7-membered ring or        a bicyclic 9- to 12-membered ring, wherein if the heterocyclic        ring is substituted then the heterocyclic ring is substituted        with 1-4 R¹⁶;    -   or R⁷ and R⁹ are taken together with the intervening atoms to        which they are attached to form an unsubstituted or substituted        monocyclic 4- to 7-membered heterocyclic ring or an        unsubstituted or substituted bicyclic 9- to 12-membered        heterocyclic ring, wherein if the heterocyclic ring is        substituted then the heterocyclic ring is substituted with 1-4        R¹⁶;    -   each R¹⁰, R¹¹, R¹² and R¹³ is independently hydrogen, halogen,        unsubstituted or substituted C₁-C₄alkyl, unsubstituted or        substituted C₂-C₄alkenyl, unsubstituted or substituted        C₁-C₄alkoxy, unsubstituted or substituted C₁-C₄fluoroalkyl,        unsubstituted or substituted C₁-C₄fluoroalkoxy, unsubstituted or        substituted monocyclic carbocycle, unsubstituted or substituted        monocyclic heterocycle, —CN, —OH, —CO₂R¹⁴, —CH₂CO₂R¹⁴,        —C(═O)NR¹⁴R¹⁵, —CH₂C(═O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —CH₂NR¹⁴R¹⁵,        —NR¹⁴C(═O)R¹⁵, —CH₂NR¹⁴C(═O)R¹⁵, —SR¹⁴, —S(═O)R¹⁵, —SO₂R¹⁵, or        —SO₂NR¹⁴R¹⁵, wherein if any group of R¹⁰, R¹¹, R¹² and R¹³ is        substituted then the substituted group of R¹⁰, R¹¹, R¹² and R¹³        is substituted with 1-4 R¹⁶;    -   each R¹⁶ is independently halogen, C₁-C₆alkyl, heterocycle, —CN,        —OR¹⁴, —CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —NR¹⁴C(═O)R¹⁵, —SR¹⁴,        —S(═O)R¹⁵, —SO₂R¹⁵, or —SO₂NR¹⁴R¹⁵;    -   each R¹⁴ is independently selected from H, unsubstituted or        substituted C₁-C₆alkyl, unsubstituted or substituted        C₁-C₆heteroalkyl, substituted or unsubstituted unsubstituted or        substituted C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl;    -   each R¹⁵ is independently selected from H, unsubstituted or        substituted C₁-C₆alkyl, unsubstituted or substituted        C₁-C₆heteroalkyl, substituted or unsubstituted unsubstituted or        substituted C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl; or R¹⁴ and R¹⁵ are        taken together with the N atom to which they are attached to a        substituted or unsubstituted N-containing heterocycle;    -   m is 1, 2, 3, or 4.

In some embodiments, a compound that has the structure of Formula (I),or a pharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof:

-   -   wherein:    -   R¹ and R² are taken together with the carbon atom to which they        are attached to form —C(═O)—;    -   or R¹ and R² are each independently selected from the group        consisting of hydrogen, and unsubstituted or substituted        C₁-C₆alkyl;    -   R^(A) is hydrogen, halogen, unsubstituted or substituted        C₁-C₆alkyl, unsubstituted or substituted C₂-C₆alkenyl,        unsubstituted or substituted C₂-C₆alkynyl, unsubstituted or        substituted C₁-C₆heteroalkyl, unsubstituted or substituted        monocyclic carbocycle, unsubstituted or substituted bicyclic        carbocycle, unsubstituted or substituted monocyclic heterocycle,        or unsubstituted or substituted bicyclic heterocycle, wherein if        R^(A) is substituted then R^(A) is substituted with 1-2 R¹⁰ and        0-2 R¹¹;    -   R^(B) is unsubstituted or substituted C₁-C₆alkyl, unsubstituted        or substituted C₂-C₆alkenyl, unsubstituted or substituted        C₂-C₆alkynyl, unsubstituted or substituted C₁-C₆heteroalkyl,        unsubstituted or substituted monocyclic carbocycle,        unsubstituted or substituted bicyclic carbocycle, unsubstituted        or substituted monocyclic heterocycle, unsubstituted or        substituted bicyclic heterocycle, wherein if R^(B) is        substituted then R^(B) is substituted with 1-2 R¹² and 0-2 R¹³;    -   A¹, A², and A³ are independently CR^(C) or N;        -   each R^(C) is independently hydrogen, halogen, unsubstituted            or substituted C₁-C₄alkyl, unsubstituted or substituted            C₁-C₄fluoroalkyl, unsubstituted or substituted C₁-C₄alkoxy,            unsubstituted or substituted C₁-C₄fluoroalkoxy, —CN, —OH,            —CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —NR¹⁴C(═O)R¹⁵, —SR¹⁴,            —S(═O)R¹⁵, —SO₂R¹⁵ or —SO₂NR¹⁴R¹⁵;    -   R³ and R⁴ are independently hydrogen, unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted        C₁-C₆fluoroalkyl, or unsubstituted or substituted        C₃-C₆cycloalkyl, wherein any substituted group of R³ and R⁴ is        substituted with 1-4 R¹⁶;    -   or R³ and R⁴ are taken together with the nitrogen atom to which        they are attached to form an unsubstituted or substituted        monocyclic or bicyclic heterocyclic ring, wherein if the        heterocyclic ring is substituted then the heterocyclic ring is        substituted with 1-4 R¹⁶;    -   R⁵, R⁶, R⁷, and R⁸ are each independently selected from the        group consisting of hydrogen, unsubstituted or substituted C₁-C₆        alkyl, and unsubstituted or substituted C₁-C₆fluoroalkyl,        unsubstituted or substituted monocyclic carbocycle,        unsubstituted or substituted monocyclic heterocycle, wherein any        substituted group of R⁵, R⁶, R⁷, and R⁸ is substituted with 1-4        R¹⁶;    -   R⁹ is hydrogen, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or unsubstituted or substituted benzyl, wherein if        R⁹ is substituted then R⁹ is substituted with 1-4 R¹⁶;    -   or R⁴ and any one of R⁵, R⁷, or R⁹ are taken together with the        intervening atoms to which they are attached to form an        unsubstituted or substituted monocyclic 4- to 7-membered        heterocyclic ring or an unsubstituted or substituted bicyclic 9-        to 12-membered heterocyclic ring, wherein if the heterocyclic        ring is substituted then the heterocyclic ring is substituted        with 1-4 R¹⁶;    -   or R⁵ and any one of R⁶, R⁷ or R⁹ are taken together with the        intervening atoms to which they are attached to form an        unsubstituted or substituted monocyclic 4- to 7-membered ring or        a bicyclic 9- to 12-membered ring, wherein if the heterocyclic        ring is substituted then the heterocyclic ring is substituted        with 1-4 R¹⁶;    -   or R⁷ and R⁹ are taken together with the intervening atoms to        which they are attached to form an unsubstituted or substituted        monocyclic 4- to 7-membered heterocyclic ring or an        unsubstituted or substituted bicyclic 9- to 12-membered        heterocyclic ring, wherein if the heterocyclic ring is        substituted then the heterocyclic ring is substituted with 1-4        R¹⁶;    -   each R¹⁰, R¹¹, R¹² and R¹³ is independently hydrogen, halogen,        unsubstituted or substituted C₁-C₄alkyl, unsubstituted or        substituted C₁-C₄alkoxy, unsubstituted or substituted        C₁-C₄fluoroalkyl, unsubstituted or substituted        C₁-C₄fluoroalkoxy, unsubstituted or substituted monocyclic        carbocycle, unsubstituted or substituted monocyclic heterocycle,        —CN, —OH, —CO₂R¹⁴, —CH₂CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵, —CH₂C(═O)NR¹⁴R¹⁵,        —NR¹⁴R¹⁵, —CH₂NR¹⁴R¹⁵, —NR¹⁴C(═O)R¹⁵, —CH₂NR¹⁴C(═O)R¹⁵, —SR¹⁴,        —S(═O)R¹⁵, —SO₂R¹⁵, or —SO₂NR¹⁴R¹⁵, wherein if any group of R¹⁰,        R¹¹, R¹² and R¹³ is substituted then the substituted group of        R¹⁰, R¹¹, R¹² and R¹³ is substituted with 1-4 R¹⁶;    -   each R¹⁶ is independently halogen, C₁-C₆alkyl, heterocycle, —CN,        —OR¹⁴, —CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —NR¹⁴C(═O)R¹⁵, —SR¹⁴,        —S(═O)R¹⁵, —SO₂R¹⁵, or —SO₂NR¹⁴R¹⁵;    -   each R¹⁴ is independently selected from H, unsubstituted or        substituted C₁-C₆alkyl, unsubstituted or substituted        C₁-C₆heteroalkyl, substituted or unsubstituted unsubstituted or        substituted C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl;    -   each R¹⁵ is independently selected from H, unsubstituted or        substituted C₁-C₆alkyl, unsubstituted or substituted        C₁-C₆heteroalkyl, substituted or unsubstituted unsubstituted or        substituted C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl; or R¹⁴ and R¹⁵ are        taken together with the N atom to which they are attached to a        substituted or unsubstituted N-containing heterocycle;    -   m is 1, 2, 3, or 4.

For any and all of the embodiments, substituents are selected from amonga subset of the listed alternatives. For example, in some embodiments, mis 1, 2, 3, or 4. In other embodiments, m is 1, 2, or 3. In some otherembodiments, m is 1 or 2. In yet other embodiments, m is 1.

In some embodiments, R¹ and R² are hydrogen; or R¹ and R² are takentogether with the carbon atom to which they are attached to form—C(═O)—; m is 1 or 2.

In some embodiments, R¹ and R² are taken together with the carbon atomto which they are attached to form —C(═O)—; m is 1 or 2.

In some embodiments, R¹ and R² are hydrogen; m is 1 or 2.

In some embodiments, A¹, A², and A³ are CR^(C).

In some embodiments, A¹ is N; and A² and A³ are CR^(C).

In some embodiments, A¹ and A³ are CR^(C); and A² is N.

In some embodiments, A¹ and A² are CR^(C); and A³ is N.

In some embodiments, A¹ and A² are N; and A³ is CR^(C).

In some embodiments, A¹ and A³ are N; and A² is CR^(C).

In some embodiments, R³ and R⁴ are each independently selected from thegroup consisting of hydrogen, unsubstituted or substituted C₁-C₆ alkyl,and unsubstituted or substituted C₁-C₆fluoroalkyl, wherein anysubstituted group of R³ and R⁴ is substituted with 1-4 R¹⁶.

In some embodiments, R³ is hydrogen; R⁶ is hydrogen; and R⁸ is hydrogen.

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments, R¹ and R² are taken together with the carbon atomto which they are attached to form a —C(═O)—.

In some embodiments, the compound of Formula (I) has the structure ofFormula (Ia), or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof:

In some embodiments, the compound of Formula (I) has the structure ofFormula (Ib), or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof:

In some embodiments, the compound of Formula (I) has the structure ofFormula (Ic), or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof:

In some embodiments, the compound of Formula (I) has the structure ofFormula (Id), or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof:

In some embodiments, the compound of Formula (I) has the structure ofFormula (Ie), or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof:

In some embodiments, the compound of Formula (I) has the structure ofFormula (If), or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof:

In some embodiments, R¹⁰ and R¹¹ are hydrogen.

In some embodiments, the compound of Formula (I) has the structure ofFormula (Ig), or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof:

In some embodiments, the compound of Formula (I) has the structure ofFormula (Ih), or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof:

In some embodiments, the compound of Formula (I) has the structure ofFormula (Ii), or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof:

In some embodiments, the compound of Formula (I) has the structure ofFormula (Ij), or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof:

In some embodiments, the compound of Formula (I) has the structure ofFormula (Ik), or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof:

In some embodiments, the compound of Formula (I) has the structure ofFormula (Il), or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof:

In some embodiments, each R^(C) is independently hydrogen, F, Cl, Br,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl,tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy,ethoxy, trifluormethoxy, —CN, —OH, —CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵,—C(═NOR¹⁴)R¹⁵, —SR, —S(═O)(C₁-C₄alkyl), —SO₂(C₁-C₄alkyl), or—SO₂NR¹⁴R¹⁵.

In some embodiments, each R^(C) is independently hydrogen, F, Cl, Br,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl,tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy,ethoxy, trifluormethoxy, —CN, or —OH.

In some embodiments, R^(A) is hydrogen, halogen, unsubstituted orsubstituted C₁-C₆alkyl, unsubstituted or substituted C₂-C₆alkenyl,unsubstituted or substituted C₂-C₆alkynyl, or unsubstituted orsubstituted C₁-C₆heteroalkyl, wherein if R^(A) is substituted then R^(A)is substituted with 1-2 R¹⁰ and 0-2 R¹¹.

In some embodiments, R^(A) is a cyclic ring that is an unsubstituted orsubstituted monocyclic carbocycle, unsubstituted or substituted bicycliccarbocycle, unsubstituted or substituted monocyclic heterocycle, orunsubstituted or substituted bicyclic heterocycle, wherein if R^(A) issubstituted then R^(A) is substituted with 1-2 R¹⁰ and 0-2 R¹¹.

In some embodiments, R^(A) is a cyclic ring that is an unsubstituted orsubstituted monocyclic carbocycle, or unsubstituted or substitutedmonocyclic heterocycle, wherein if R^(A) is substituted then R^(A) issubstituted with 1-2 R¹⁰ and 0-2 R¹¹.

In some embodiments, R^(A) is a cyclic ring that is an unsubstituted orsubstituted monocyclic carbocycle, or unsubstituted or substitutedmonocyclic heterocycle, wherein if R^(A) is substituted then R^(A) issubstituted with R¹⁰ and R¹¹, wherein R¹⁰ and R¹¹ are in anortho-relationship on R^(A). In some embodiments, R^(A) is a cyclic ringthat is an unsubstituted or substituted monocyclic carbocycle, orunsubstituted or substituted monocyclic heterocycle, wherein if R^(A) issubstituted then R^(A) is substituted with R¹⁰ and R¹¹, wherein R¹⁰ andR¹¹ are in a meta-relationship on R^(A). In some embodiments, R^(A) is acyclic ring that is an unsubstituted or substituted monocycliccarbocycle, or unsubstituted or substituted monocyclic heterocycle,wherein if R^(A) is substituted then R^(A) is substituted with R¹⁰ andR¹¹, wherein R¹⁰ and R¹¹ are in a para-relationship on R^(A).

In some embodiments, R^(A) is an unsubstituted or substituted monocycliccarbocycle, wherein if R^(A) is substituted then R^(A) is substitutedwith R¹⁰ and R¹¹, wherein R¹⁰ and R¹¹ are in a meta-relationship onR^(A). In some embodiments, R^(A) is an unsubstituted or substitutedmonocyclic heterocycle, wherein if R^(A) is substituted then R^(A) issubstituted with R¹⁰ and R¹¹, wherein R¹⁰ and R¹¹ are in ameta-relationship on R^(A).

In some embodiments, R^(A) is an unsubstituted or substituted monocycliccarbocycle, or unsubstituted or substituted bicyclic carbocycle, whereinif R^(A) is substituted then R^(A) is substituted with 1-2 R¹⁰ and 0-2R¹¹.

In some embodiments, R^(A) is an unsubstituted or substituted monocycliccarbocycle selected from unsubstituted or substituted phenyl,unsubstituted or substituted cyclopropyl, unsubstituted or substitutedcyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted orsubstituted cyclopentenyl, unsubstituted or substituted cyclohexyl orunsubstituted or substituted cyclohexenyl, wherein if R^(A) issubstituted then R^(A) is substituted with 1-2 R¹⁰ and 0-2 R¹¹.

In some embodiments, R^(A) is an unsubstituted or substituted phenyl,wherein if R^(A) is substituted then R^(A) is substituted with 1-2 R¹⁰and 0-2 R¹¹.

In some embodiments, R^(A) is

n is 0, 1, or 2.

In some embodiments, R^(A) is

n is 0, 1, or 2.

In some embodiments, R^(A) is an unsubstituted or substituted bicycliccarbocycle selected from unsubstituted or substituted naphthyl,unsubstituted or substituted indanyl, unsubstituted or substitutedindenyl, or unsubstituted or substituted tetrahyodronaphthyl, wherein ifR^(A) is substituted then R^(A) is substituted with 1-2 R¹⁰ and 0-2 R¹¹.

In some embodiments, R^(A) is an unsubstituted or substituted monocyclicheterocycle containing 1-4 N atoms and 0 or 1 O or S atom, unsubstitutedor substituted monocyclic heterocycle containing 0-4 N atoms and 1 O orS atoms, unsubstituted or substituted bicyclic heterocycle containing1-4 N atoms and 0 or 1 O or S atoms, or unsubstituted or substitutedbicyclic heterocycle containing 0-4 N atoms and 1 O or S atoms, whereinif R^(A) is substituted then R^(A) is substituted with 1-2 R¹⁰ and 0-2R¹¹.

In some embodiments, R^(A) is an unsubstituted or substituted monocyclicheterocycle selected from unsubstituted or substituted furanyl,unsubstituted or substituted pyrrolyl, unsubstituted or substitutedoxazolyl, unsubstituted or substituted thiazolyl, unsubstituted orsubstituted imidazolyl, unsubstituted or substituted pyrazolyl,unsubstituted or substituted triazolyl, unsubstituted or substitutedtetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted orsubstituted isothiazolyl, unsubstituted or substituted oxadiazolyl,unsubstituted or substituted thiadiazolyl, unsubstituted or substitutedpyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted orsubstituted pyrazinyl, unsubstituted or substituted pyridazinyl, andunsubstituted or substituted triazinyl, wherein if R^(A) is substitutedthen R^(A) is substituted with 1-2 R¹⁰ and 0-2 R¹¹.

In some embodiments, R^(A) is

n is 0, 1, or 2

In some embodiments, R^(A) is

n is 0, 1, or 2.

In some embodiments, R^(A) is

n is 0, 1, or 2.

In some embodiments, R^(A) is an unsubstituted or substituted bicyclicheterocycle selected from unsubstituted or substituted quinolinyl,unsubstituted or substituted isoquinolinyl, unsubstituted or substitutedquinazolinyl, unsubstituted or substituted quinoxalinyl, unsubstitutedor substituted naphthyridinyl, unsubstituted or substituted indolyl,unsubstituted or substituted indazolyl, unsubstituted or substitutedbenzoxazolyl, unsubstituted or substituted benzisoxazolyl, unsubstitutedor substituted benzofuranyl, unsubstituted or substituted benzothienyl,unsubstituted or substituted benzothiazolyl, unsubstituted orsubstituted benzimidazolyl, unsubstituted or substituted purinyl,unsubstituted or substituted cinnolinyl, unsubstituted or substitutedphthalazinyl, unsubstituted or substituted pteridinyl, unsubstituted orsubstituted pyridopyrimidinyl, unsubstituted or substitutedpyrazolopyrimidinyl, unsubstituted or substituted azaindolyl,unsubstituted or substituted indolinyl, unsubstituted or substitutedisoindolinyl, unsubstituted or substituted indolinonyl, unsubstituted orsubstituted isoindolinonyl, or unsubstituted or substitutedquinolinonyl, wherein if R^(A) is substituted then R^(A) is substitutedwith 1-2 R¹⁰ and 0-2 R¹¹.

In some embodiments, each R¹⁰ is independently hydrogen, halogen,unsubstituted or substituted C₁-C₄alkyl, unsubstituted or substitutedC₁-C₄alkoxy, unsubstituted or substituted C₁-C₄fluoroalkyl,unsubstituted or substituted C₁-C₄fluoroalkoxy, unsubstituted orsubstituted monocyclic carbocycle, unsubstituted or substitutedmonocyclic heterocycle, —CN, —OH, —CO₂R¹⁴, —CH₂CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵,—CH₂C(═O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —CH₂NR¹⁴R¹⁵, —NR¹⁴C(═O)R¹⁵,—CH₂NR¹⁴C(═O)R¹⁵, —SR¹⁴, —S(═O)R¹⁵, —SO₂R¹⁵, or —SO₂NR¹⁴R¹⁵, wherein ifR¹⁰ is substituted then R¹⁰ is substituted with 1-4 R¹⁶; each R¹¹ isindependently hydrogen, halogen, unsubstituted or substitutedC₁-C₄alkyl, unsubstituted or substituted C₁-C₄alkoxy, unsubstituted orsubstituted C₁-C₄fluoroalkyl, unsubstituted or substitutedC₁-C₄fluoroalkoxy, —CN, or —OH, wherein if R¹¹ is substituted then R¹¹is substituted with 1-4 R¹⁶.

In some embodiments, each R¹⁰ is independently hydrogen, halogen,unsubstituted or substituted C₁-C₄alkyl, unsubstituted or substitutedC₁-C₄alkoxy, C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, unsubstituted orsubstituted phenyl, unsubstituted or substituted monocyclic heterocycle,—CN, —OH, —CO₂R¹⁴, —CH₂CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵, —CH₂C(═O)NR¹⁴R¹⁵,—NR¹⁴R¹⁵, —CH₂NR¹⁴R¹⁵, —NR¹⁴C(═O)R¹⁵, or —CH₂NR¹⁴C(═O)R¹⁵, wherein ifR¹⁰ is substituted then R¹⁰ is substituted with 1-4 R¹⁶; and each R¹¹ isindependently hydrogen, halogen, unsubstituted or substitutedC₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkoxy, or —CN,wherein if R¹¹ is substituted then R¹¹ is substituted with —OR¹⁴ or—NR¹⁴R¹⁵.

In some embodiments, each R¹⁰ is independently hydrogen, F, Cl, —CH₃,—OCH₃, —CF₃, —OCF₃, —CN, —OH, —CO₂H, —CH₂CO₂H, —C(═O)NH₂, —CH₂C(═O)NH₂,—NH₂, —CH₂NH₂, —NHC(═O)CH₃, or —CH₂NHC(═O)CH₃; and each R¹¹ isindependently hydrogen, F, Cl, —CH₃, —OCH₃, —CF₃, —OCF₃, or —CN.

In some embodiments, R^(B) is a cyclic ring that is an unsubstituted orsubstituted monocyclic carbocycle, unsubstituted or substituted bicycliccarbocycle, unsubstituted or substituted monocyclic heterocycle,unsubstituted or substituted bicyclic heterocycle, wherein if R^(B) issubstituted then R^(B) is substituted with 1-2 R¹² and 0-2 R¹³.

In some embodiments, R^(B) is a cyclic ring that is an unsubstituted orsubstituted monocyclic carbocycle, or unsubstituted or substitutedmonocyclic heterocycle, wherein if R^(B) is substituted then R^(B) issubstituted with 1-2 R¹² and 0-2 R¹³.

In some embodiments, R^(B) is a cyclic ring that is an unsubstituted orsubstituted monocyclic carbocycle, or unsubstituted or substitutedmonocyclic heterocycle, wherein if R^(B) is substituted then R^(B) issubstituted with R¹² and R¹³, wherein R¹² and R¹³ are in anortho-relationship on R^(B). In some embodiments, R^(B) is a cyclic ringthat is an unsubstituted or substituted monocyclic carbocycle, orunsubstituted or substituted monocyclic heterocycle, wherein if R^(B) issubstituted then R^(B) is substituted with R¹² and R¹³, wherein R¹² andR¹³ are in a meta-relationship on R^(B). In some embodiments, R^(B) is acyclic ring that is an unsubstituted or substituted monocycliccarbocycle, or unsubstituted or substituted monocyclic heterocycle,wherein if R^(B) is substituted then R^(B) is substituted with R¹² andR¹³, wherein R¹² and R¹³ are in a para-relationship on R^(B).

In some embodiments, R^(B) is an unsubstituted or substituted monocycliccarbocycle, wherein if R^(B) is substituted then R^(B) is substitutedwith R¹² and R¹³, wherein R¹² and R¹³ are in a meta-relationship onR^(B). In some embodiments, R^(B) is an unsubstituted or substitutedmonocyclic heterocycle, wherein if R^(B) is substituted then R^(B) issubstituted with R¹² and R¹³, wherein R¹² and R¹³ are in ameta-relationship on R^(B).

In some embodiments, R^(B) is an unsubstituted or substituted monocycliccarbocycle, or unsubstituted or substituted bicyclic carbocycle, whereinif R^(B) is substituted then R^(B) is substituted with 1-2 R¹² and 0-2R¹³.

In some embodiments, R^(B) is an unsubstituted or substituted monocycliccarbocycle selected from unsubstituted or substituted phenyl,unsubstituted or substituted cyclopropyl, unsubstituted or substitutedcyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted orsubstituted cyclopentenyl, unsubstituted or substituted cyclohexyl, orunsubstituted or substituted cyclohexenyl, wherein if R^(B) issubstituted then R^(B) is substituted with 1-2 R¹² and 0-2 R¹³.

In some embodiments, R^(B) is an unsubstituted or substituted phenyl,wherein if R^(B) is substituted then R^(B) is substituted with 1-2 R¹²and 0-2 R¹³.

In some embodiments, R^(B) is

t is 0, 1, or 2.

In some embodiments, R^(B) is

t is 0, 1, or 2.

In some embodiments, R^(B) is an unsubstituted or substituted bicycliccarbocycle selected from unsubstituted or substituted naphthyl,unsubstituted or substituted indanyl, unsubstituted or substitutedindenyl, or unsubstituted or substituted tetrahyodronaphthyl, wherein ifR^(B) is substituted then R^(B) is substituted with 1-2 R¹² and 0-2 R¹³.

In some embodiments, R^(B) is an unsubstituted or substituted monocyclicheterocycle containing 1-4 N atoms and 0 or 1 O or S atom, unsubstitutedor substituted monocyclic heterocycle containing 0-4 N atoms and 1 O orS atoms, unsubstituted or substituted bicyclic heterocycle containing1-4 N atoms and 0 or 1 O or S atoms, or unsubstituted or substitutedbicyclic heterocycle containing 0-4 N atoms and 1 O or S atoms, whereinif R^(B) is substituted then R^(B) is substituted with 1-2 R¹² and 0-2R¹³.

In some embodiments, R^(B) is an unsubstituted or substituted monocyclicheterocycle selected from unsubstituted or substituted furanyl,unsubstituted or substituted pyrrolyl, unsubstituted or substitutedoxazolyl, unsubstituted or substituted thiazolyl, unsubstituted orsubstituted imidazolyl, unsubstituted or substituted pyrazolyl,unsubstituted or substituted triazolyl, unsubstituted or substitutedtetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted orsubstituted isothiazolyl, unsubstituted or substituted oxadiazolyl,unsubstituted or substituted thiadiazolyl, unsubstituted or substitutedpyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted orsubstituted pyrazinyl, unsubstituted or substituted pyridazinyl, andunsubstituted or substituted triazinyl, wherein if R^(B) is substitutedthen R^(B) is substituted with 1-2 R¹² and 0-2 R¹³.

In some embodiments, R^(B) is

t is 0, 1, or 2

In some embodiments, R^(B) is

t is 0, 1, or 2.

In some embodiments, R^(B)

t is 0, 1, or 2.

In some embodiments, R^(B) is an unsubstituted or substituted bicyclicheterocycle selected from unsubstituted or substituted quinolinyl,unsubstituted or substituted isoquinolinyl, unsubstituted or substitutedquinazolinyl, unsubstituted or substituted quinoxalinyl, unsubstitutedor substituted naphthyridinyl, unsubstituted or substituted indolyl,unsubstituted or substituted indazolyl, unsubstituted or substitutedbenzoxazolyl, unsubstituted or substituted benzisoxazolyl, unsubstitutedor substituted benzofuranyl, unsubstituted or substituted benzothienyl,unsubstituted or substituted benzothiazolyl, unsubstituted orsubstituted benzimidazolyl, unsubstituted or substituted purinyl,unsubstituted or substituted cinnolinyl, unsubstituted or substitutedphthalazinyl, unsubstituted or substituted pteridinyl, unsubstituted orsubstituted pyridopyrimidinyl, unsubstituted or substitutedpyrazolopyrimidinyl, unsubstituted or substituted azaindolyl,unsubstituted or substituted indolinyl, unsubstituted or substitutedisoindolinyl, unsubstituted or substituted indolinonyl, unsubstituted orsubstituted isoindolinonyl, or unsubstituted or substitutedquinolinonyl, wherein if R^(B) is substituted then R^(B) is substitutedwith 1-2 R¹² and 0-2 R¹³.

In some embodiments, each R¹² is independently hydrogen, halogen,unsubstituted or substituted C₁-C₄alkyl, unsubstituted or substitutedC₁-C₄alkoxy, unsubstituted or substituted C₁-C₄fluoroalkyl,unsubstituted or substituted C₁-C₄fluoroalkoxy, unsubstituted orsubstituted monocyclic carbocycle, unsubstituted or substitutedmonocyclic heterocycle, —CN, —OH, —CO₂R¹⁴, —CH₂CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵,—CH₂C(═O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —CH₂NR¹⁴R¹⁵, —NR¹⁴C(═O)R¹⁵,—CH₂NR¹⁴C(═O)R¹⁵, —SR¹⁴, —S(═O)R¹⁵, —SO₂R¹⁵, or —SO₂NR¹⁴R¹⁵, wherein ifR¹² is substituted then R¹² is substituted with R¹⁶; each R¹³ isindependently hydrogen, halogen, unsubstituted or substitutedC₁-C₄alkyl, unsubstituted or substituted C₁-C₄alkoxy, unsubstituted orsubstituted C₁-C₄fluoroalkyl, unsubstituted or substitutedC₁-C₄fluoroalkoxy, unsubstituted or substituted monocyclic carbocycle,unsubstituted or substituted monocyclic heterocycle, —CN, —OH, whereinif R¹³ is substituted then R¹³ is substituted with R¹⁶.

In some embodiments, each R¹² is independently hydrogen, F, Cl, —CH₃,—OCH₃, —CF₃, —OCF₃, —CN, —OH, —CO₂H, —CH₂CO₂H, —C(═O)NH₂, —CH₂C(═O)NH₂,—NH₂, —CH₂NH₂, or —SO₂NH₂; each R¹³ is independently hydrogen, F, Cl,—CH₃, —OCH₃, —CF₃, —OCF₃, —CN, or —OH.

In some embodiments, each R¹⁰ is independently hydrogen, F, Cl, —CH₃,—OCH₃, —CF₃, —OCF₃, —CN, —OH, —CO₂H, —CH₂CO₂H, —C(═O)NH₂, —CH₂C(═O)NH₂,—NH₂, —CH₂NH₂, —NHC(═O)CH₃, or —CH₂NHC(═O)CH₃; and each R¹¹ isindependently hydrogen, F, Cl, —CH₃, —OCH₃, —CF₃, —OCF₃, or —CN.

In some embodiments, R⁴ is hydrogen, or unsubstituted or substitutedC₁-C₆ alkyl, wherein if R⁴ is substituted then it is substituted with1-4 R¹⁶; R⁵ is hydrogen, or unsubstituted or substituted C₁-C₆ alkyl,wherein if R⁵ is substituted then it is substituted with 1-4 R¹⁶; R⁷ ishydrogen; or R⁴ and R⁵ are taken together with the nitrogen atom towhich they are attached to form a monocyclic 4- to 7-memberedheterocyclic ring, wherein if the heterocyclic ring is substituted thenthe heterocyclic ring is substituted with 1-4 R¹⁶; or R⁴ and R⁷ aretaken together with the nitrogen atom to which they are attached to forma monocyclic 4- to 7-membered heterocyclic ring, wherein if theheterocyclic ring is substituted then the heterocyclic ring issubstituted with 1-4 R¹⁶

In some embodiments, R⁴ is hydrogen, methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, sec-butyl, or tert-butyl; R⁵ is hydrogen, methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or tert-butyl;R⁷ is hydrogen; or R⁴ and R⁵ are taken together with the nitrogen atomto which they are attached to form an unsubstituted or substitutedmonocyclic 4- to 7-membered heterocyclic ring selected fromunsubstituted or substituted azetidinyl, unsubstituted or substitutedpyrrolidinyl, unsubstituted or substituted pyrrolidinonyl, unsubstitutedor substituted piperidinyl, unsubstituted or substituted morpholinyl,unsubstituted or substituted thiomorpholinyl, unsubstituted orsubstituted piperazinyl, or unsubstituted or substituted azepanyl,wherein if the heterocyclic ring is substituted then the heterocyclicring is substituted with 1-4 R¹⁶; or R⁴ and R⁷ are taken together withthe nitrogen atom to which they are attached to form an unsubstituted orsubstituted monocyclic 4- to 7-membered heterocyclic ring selected fromunsubstituted or substituted azetidinyl, unsubstituted or substitutedpyrrolidinyl, unsubstituted or substituted pyrrolidinonyl, unsubstitutedor substituted piperidinyl, unsubstituted or substituted morpholinyl,unsubstituted or substituted thiomorpholinyl, unsubstituted orsubstituted piperazinyl, or unsubstituted or substituted azepanyl,wherein if the heterocyclic ring is substituted then the heterocyclicring is substituted with 1-4 R¹⁶.

In some embodiments, R⁴ and R⁵ are taken together with the nitrogen atomto which they are attached to form:

p is 1, 2, or 3; and q is 0, 1, or 2.

In some embodiments, R⁴ and R⁵ are taken together with the nitrogen atomto which they are attached to form:

In some embodiments, R⁴ and R⁵ are taken together with the nitrogen atomto which they are attached to form:

In some embodiments, R⁴ and R⁵ are taken together with the nitrogen atomto which they are attached to form:

In some embodiments, R⁴ and R⁵ are taken together with the nitrogen atomto which they are attached to form:

In some embodiments,

p is 1, 2, or 3; and q is 0, 1, or 2.

In some embodiments,

p is 1, 2, or 3; and q is 0, 1, or 2.

In some embodiments, R⁴ is hydrogen, methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, sec-butyl, or tert-butyl; R⁵ is hydrogen, methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or tert-butyl;and R⁷ is hydrogen.

In some embodiments,

p is 1, 2, or 3; and q is 0, 1, or 2.

In some embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3.

In some embodiments, q is 0. In some embodiments, q is 1. In someembodiments, q is 2.

In some embodiments,

In some embodiments,

p is 1, 2, or 3; and q is 0, 1, or 2.

In some embodiments,

In some embodiments,

p is 1, 2, or 3; and q is 0, 1, or 2.

In some embodiments,

In some embodiments, R⁹ is hydrogen, unsubstituted or substituted C₁-C₆alkyl, or unsubstituted or substituted benzyl, wherein if R⁹ issubstituted then R⁹ is substituted with 1-4 R¹⁶.

In some embodiments, R⁹ is methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, sec-butyl, tert-butyl, or benzyl.

In some embodiments, R⁹ is methyl, or ethyl.

In some embodiments, R⁹ is methyl.

In some embodiments, R⁹ is as described in Table 1 or Table 2.

In some embodiments, R¹⁰ is as described in Table 1 or Table 2.

In some embodiments, R¹¹ is as described in Table 1 or Table 2.

In some embodiments, R¹² is as described in Table 1 or Table 2.

In some embodiments, R¹³ is as described in Table 1 or Table 2.

In some embodiments, R^(A) is as described in Table 3. In someembodiments, R^(B) is as described in Table 3.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

Exemplary compounds of Formula (I) include the compounds described inthe following Tables:

TABLE 1

Cpd No. R R⁹ R¹⁰ R¹¹ R¹² R¹³ 1-1

CH₃ 3-CH₃ 5-Cl 3′-OH H 1-2

CH₃ 3-Cl 5-CH₃ 3′-OH H 1-3

CH₃ 3-CH₃ 5-Cl 3′-OH H 1-4

CH₃ 3-CH₃ 5-F 3′-OH H 1-5

CH₃ 3-CH₃ 5-Cl 3′-OH H 1-6

CH₃ 3-OCH₃ 5-F 3′-OH H 1-7

CH₃ 3-CH₃ 5-F 3′-OH H 1-8

CH₃ 3-CH₃ 5-Cl 3′-OH 5′-CONH₂ 1-9

CH₃ 3-CH₃ 5-F 3′-OMe 5′-CN 1-10

CH₃ 3-CH₃ 5-F 3′-OH 5′-CN 1-11

CH₃ 3-CH₃ 5-F 3′-OH 6′-CH₃ 1-12

CH₃ 3-CH₃ 5-F 3′-CN 2′-CH₃ 1-13

CH₃ 3-CH₃ 5-F 3′-F 2′-CH₃ 1-14

CH₃ 3-CH₃ 5-F 3′-CN 6′-CH₃ 1-15

CH₃ 3-CH₃ 5-F 3′-CN 5′-F 1-16

CH₃ 3-CH₃ 5-F 3-CN H 1-17

CH₃ 3-CH₃ 5-F 3′-OMe 5′-F 1-18

CH₃ 3-F H 3′-OH H 1-19

CH₃ 3-CH₃ 5-F 3′-CN 5′-OMe 1-20

CH₃ 3-CH₃ 5-F 3′-CN 5′-F 1-21

CH₃ 3-CH₃ 5-F 3′-CN 5′-OMe 1-22

CH₃ 3-F 5-F 3′-CN 5′-F 1-23

CH₃ 3-F 5-F 3′-OH 2′-F 1-24

CH₃ 3-CH₃ 5-F 3′-CN 5′-F 1-25

CH₃ 3-F 5-F 3′-CN 2′-F 1-26

CH₃ 3-F 5-F 3′-CONH₂ 5′-F 1-27

CH₃ 3-F 5-F 3′-CN 6′-OMe 1-28

CH₃ 3-F 5-F 3′-CN 6′-F 1-29

CH₃ 3-CH₃ 5-F 3′-OH H 1-30

CH₃ 3-F 5-F 3′-CN 5′-OMe 1-31

CH₃ 3-F 5-F 3′-OH 2′-Cl 1-32

CH₃ 3-F 5-F 3′-CN 5′-OMe 1-33

CH₃ 3-CH₃ 5-F 3′-CONH₂ 5′-F 1-34

CH₃ 3-F 5-OH 3′-CN 5′-F 1-35

CH₃ 3-CH₂CH₂OH 5-F 3′-CN 5′-F 1-36

CH₃ 3-CH₃ 5-F 3′-F 5′-CO₂H 1-37

CH₃ 3-CH₃ 5-F 3′-F 5′-O(CH₂)₃CO₂H 1-38

CH₃ 3-F 5-F 3′-OH 5′-CN 1-39

CH₃ 3-OCH₂CH₂OH 5-F 3′-CN 5′-F 1-40

CH₃ 3-CH₃ 5-F 3′-CN 5′-CF₃ 1-41

CH₃ 3-CH₃ 5-F 3′-OH 2′-Cl 1-42

CH₃ 3-OCH₂CH₂OCH₃ 5-F 3′-CN 5′-F 1-43

CH₃ 3-CH₃ 5-F 3′-OH 2′-CH₂OCH₃ 1-44

CH₃ 3-CH₃ 5-F 3′-CO₂H H 1-45

CH₃ 3-CH₂CH₂OH 5-F 3′-CN 2-CH₃ 1-46

CH₃ 3-CH₃ 5-F 4′-CO₂H H 1-47

CH₃ 3-CH₃ 5-F 2′-CO₂H H 1-48

CH₃ 3-CH₃ 5-F 3′-CH₂CO₂H H 1-49

CH₃ 3-CH₃ 5-F 3′-CH₂CO₂CH₃ H 1-50

CH₃ 3-CH₃ 5-F 3′-(CH₂)₂CO₂H H 1-51

CH₃ 3-CH₃ 5-F 3′-CN 2′-CH₃ 1-52

CH₃ 3-CH₃ 5-F 3′-CN 6′-CH₃ 1-53

CH₃ 3-CH₃ 5-F 3′-CONH₂ 2′-F 1-54

CH₃ 3-CH₃ 5-F 3′-CONH₂ 4′-F 1-55

CH₃ 3-F 5-F 3′-CN 5′-F 1-56

CH₃ 2-F 5-F 3′-CN 5′-F 1-57

CH₃ 2-Cl 5-CH₃ 3′-CN 5′-F 1-58

CH₃ 2-CH₃ 5-F 3′-CN 5′-F 1-59

CH₃ 3-CH₃ 5-F 3′-CH₂CO₂H 5′-F 1-60

CH₃ 3-CH₃ 5-F 3′-SO₂NH₂ H 1-61

CH₃ 3-CH₃ 5-F 3′-F 5′-F 1-62

CH₃ 3-OCH₂CO₂H 5-F 3′-F 5′-F 1-63

CH₃ 3-CH₃ 5-F 3′-F 5′-F 1-64

CH₃ 3-CH₃ 5-F 3′-OCH₃ 6′-Cl 1-65

CH₃ 3-OCH₂CO₂H 5-Cl 3′-CN 5′-F 1-66

CH₃ 3-CH₃ 5-F 3′-SONH₂ 5′-F 1-67

CH₃ 3-F 2-F 3′-CN 5′-F 1-68

CH₃ 3-CH₃ 5-F 3′-F 5′-F 1-69

CH₃ 3-C(CH₃)₂OH 5-F 3′-CN 5′-F 1-70

CH₃ 3-CH₃ 5-F 3′-CF₃ 5′-F 1-71

CH₃ 3-C(CH₃)═CH₂ 5-F 3′-CN 5′-F 1-72

CH₃ 3-CH₃ 5-F 3′-CONH₂ 4′-OH 1-73

CH₃ 3-CONMe₂ H 3′-OH H 1-74

CH₃ 3-CH₃ 5-F 3′-CH₂CONH₂ 5′-F 1-75

CH₃ 3-CH₃ 5-F 3′-CONH₂ 5′-OCH₃ 1-76

CH₃ 3-CH₃ 5-F 3′-CN 5′-CONHCH₃ 1-77

CH₃ 3-CH₃ 5-F 3′-CN 2′-OH 1-78

CH₃ 3-CH₃ 5-F 3′-CONH₂ 5′-CN 1-79

CH₃ 3-CH₃ 5-F 3′-CN 5′-F 1-80

CH₃ 3-CH₃ 5-Cl 3′-CN 5′-F 1-81

CH₃ 3-CH₃ 5-Cl 3′-CONH₂ 5′-F 1-82

CH₃ 3-Cl 5-Cl 3′-CN 5′-F 1-83

CH₃ 3-Cl 5-Cl 3′-CONH₂ 5′-F 1-84

CH₃ 3-CH₃ 5-Cl 3′-CN 2′-OH 1-85

CH₃ 3-Cl 5-Cl 3′-CN 2′-OH 1-86

CH₃ 3-Cl 5-F 3′-CN 2′-OH 1-87

CH₃ 3-Cl 5-F 3′-CN 2′-OH 1-88

CH₃ 3-Cl 5-F 3′-CONH₂ 5′-F 1-89

CH₃ 3-CH₃ 5-F 3′-F 5′-F 1-90

CH₃ 3-CH₃ 5-F 3′-CN 5′-F 1-91

CH₃ 3-CH₃ 5-F 3′-F 2′-OH

Compounds in Table 1 are named:

-   1-1:    3-(3-chloro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-2:    N-[(2S)-2-aminopropyl]-3-(3-chloro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methylquinoline-4-carboxamide;-   1-3:    N-[(2S)-2-aminobutyl]-3-(3-chloro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methylquinoline-4-carboxamide;-   1-4:    3-(3-fluoro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-5:    3-(3-chloro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2R)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-6:    3-(3-fluoro-5-methoxyphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-7:    N-[(2S)-azetidin-2-ylmethyl]-3-(3-fluoro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methylquinoline-4-carboxamide;-   1-8:    N-[(2S)-2-aminobutyl]-6-(3-carbamoyl-5-hydroxyphenyl)-3-(3-chloro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   1-9:    N-[(2S)-2-aminobutyl]-6-(3-cyano-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   1-10:    N-[(2S)-2-aminobutyl]-6-(3-cyano-5-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   1-11:    N-[(2S)-2-aminobutyl]-3-(3-fluoro-5-methylphenyl)-6-(5-hydroxy-2-methylphenyl)-N-methylquinoline-4-carboxamide;-   1-12:    N-[(2S)-2-aminobutyl]-6-(3-cyano-2-methylphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   1-13:    N-[(2S)-2-aminobutyl]-6-(3-fluoro-2-methylphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   1-14:    N-[(2S)-2-aminobutyl]-6-(5-cyano-2-methylphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   1-15:    N-[(2S)-2-aminobutyl]-6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   1-16:    6-(3-cyanophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-17:    N-[(2S)-2-aminobutyl]-6-(3-fluoro-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   1-18:    3-(3-fluorophenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-19:    N-[(2S)-2-aminopropyl]-6-(3-cyano-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   1-20:    N-[(2S)-2-aminopropyl]-6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   1-21:    6-(3-cyano-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-22:    6-(3-cyano-5-fluorophenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-23:    3-(3,5-difluorophenyl)-6-(2-fluoro-3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-24:    6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-25:    6-(3-cyano-2-fluorophenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-26:    6-(3-carbamoyl-5-fluorophenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-27:    6-(5-cyano-2-methoxyphenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-28:    6-(5-cyano-2-fluorophenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-29:    3-(3-fluoro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-(morpholin-3-ylmethyl)quinoline-4-carboxamide;-   1-30:    6-(3-cyano-5-methoxyphenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-31:    6-(2-chloro-3-hydroxyphenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-32:    N-[(2S)-2-aminobutyl]-6-(3-cyano-5-methoxyphenyl)-3-(3,5-difluorophenyl)-N-methylquinoline-4-carboxamide;-   1-33:    6-(3-carbamoyl-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-34:    6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-35:    6-(3-cyano-5-fluorophenyl)-3-[3-fluoro-5-(2-hydroxyethyl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-36:    3-fluoro-5-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]benzoic    acid;-   1-37:    4-{3-[6-(3-cyano-5-fluorophenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-3-yl]-5-fluorophenoxy}butanoic    acid;-   1-38:    N-[(2S)-2-aminobutyl]-6-(3-cyano-5-hydroxyphenyl)-3-(3,5-difluorophenyl)-N-methylquinoline-4-carboxamide;-   1-39:    6-(3-cyano-5-fluorophenyl)-3-[3-fluoro-5-(2-hydroxyethoxy)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-40:    6-[3-cyano-5-(trifluoromethyl)phenyl]-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-41:    6-(2-chloro-3-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-42:    6-(3-cyano-5-fluorophenyl)-3-[3-fluoro-5-(2-methoxyethoxy)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-43:    3-(3-fluoro-5-methylphenyl)-6-[3-hydroxy-2-(methoxymethyl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide    1-44:    3-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]benzoic    acid;-   1-45:    6-(3-cyano-2-methylphenyl)-3-[3-fluoro-5-(2-hydroxyethyl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-46:    4-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]benzoic    acid;-   1-47:    2-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]benzoic    acid;-   1-48:    2-{3-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]phenyl}acetic    acid;-   1-49: methyl    2-{3-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]phenyl}acetate;-   1-50:    3-{3-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]phenyl}propanoic    acid;-   1-51:    6-(3-cyano-2-methylphenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-52:    6-(5-cyano-2-methylphenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-53:    6-(3-carbamoyl-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-54:    6-(3-carbamoyl-4-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-55:    N-[(2S)-2-aminobutyl]-6-(3-cyano-5-fluorophenyl)-3-(3,5-difluorophenyl)-N-methylquinoline-4-carboxamide;-   1-56:    6-(3-cyano-5-fluorophenyl)-3-(2,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-57:    3-(2-chloro-5-methylphenyl)-6-(3-cyano-5-fluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide    1-58:    6-(3-cyano-5-fluorophenyl)-3-(5-fluoro-2-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide    1-59:    2-{3-fluoro-5-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]phenyl}acetic    acid;-   1-60:    3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-6-(3-sulfamoylphenyl)quinoline-4-carboxamide;-   1-61:    6-(3,5-difluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(3S)-pyrrolidin-3-yl]quinoline-4-carboxamide;-   1-62:    6-(3,5-difluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-63:    6-(6-carbamoylpyrazin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-64:    6-(2-chloro-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-65:    2-{3-chloro-5-[6-(3-cyano-5-fluorophenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-3-yl]phenoxy}acetic    acid;-   1-66:    3-(3-fluoro-5-methylphenyl)-6-(3-fluoro-5-sulfamoylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-67:    6-(3-cyano-5-fluorophenyl)-3-(2,3-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-68:    N-[(2S)-2-amino-3-methylbutyl]-6-(3,5-difluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   1-69:    6-(3-cyano-5-fluorophenyl)-3-[3-fluoro-5-(2-hydroxypropan-2-yl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-70:    N-[(2S)-2-aminobutyl]-6-[3-fluoro-5-(trifluoromethyl)phenyl]-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   1-71:    6-(3-cyano-5-fluorophenyl)-3-[3-fluoro-5-(prop-1-en-2-yl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-72:    6-(3-carbamoyl-4-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-73:    3-[3-(dimethylcarbamoyl)phenyl]-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-74:    6-[3-(carbamoylmethyl)-5-fluorophenyl]-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-75:    N-[(2S)-2-aminopropyl]-6-(3-carbamoyl-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   1-76:    3-(4-{[(2S)-2-aminopropyl](methyl)carbamoyl}-3-(3-fluoro-5-methylphenyl)quinolin-6-yl)-5-methoxybenzoic    acid;-   1-76:    6-[3-cyano-5-(methylcarbamoyl)phenyl]-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-77:    6-(3-cyano-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-78:    6-(3-carbamoyl-5-cyanophenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-79:    6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-{[(2S,4R)-4-fluoropyrrolidin-2-yl]methyl}-N-methylquinoline-4-carboxamide;-   1-80:    N-[(2S)-azetidin-2-ylmethyl]-3-(3-chloro-5-methylphenyl)-6-(3-cyano-5-fluorophenyl)-N-methylquinoline-4-carboxamide;-   1-81:    N-[(2S)-azetidin-2-ylmethyl]-6-(3-carbamoyl-5-fluorophenyl)-3-(3-chloro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   1-82:    N-[(2S)-azetidin-2-ylmethyl]-6-(3-cyano-5-fluorophenyl)-3-(3,5-dichlorophenyl)-N-methylquinoline-4-carboxamide;-   1-83:    N-[(2S)-azetidin-2-ylmethyl]-6-(3-carbamoyl-5-fluorophenyl)-3-(3,5-dichlorophenyl)-N-methylquinoline-4-carboxamide;-   1-84:    N-[(2S)-azetidin-2-ylmethyl]-3-(3-chloro-5-methylphenyl)-6-(3-cyano-2-hydroxyphenyl)-N-methylquinoline-4-carboxamide;-   1-85:    N-[(2S)-azetidin-2-ylmethyl]-6-(3-cyano-2-hydroxyphenyl)-3-(3,5-dichlorophenyl)-N-ethylquinoline-4-carboxamide;-   1-86:    N-[(2S)-azetidin-2-ylmethyl]-3-(3-chloro-5-fluorophenyl)-6-(3-cyano-2-hydroxyphenyl)-N-methylquinoline-4-carboxamide;-   1-87:    3-(3-chloro-5-fluorophenyl)-6-(3-cyano-2-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-88:    6-(3-carbamoyl-5-methylphenyl)-3-(3-chloro-5-fluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   1-89:    N-[(2S)-2-amino-4-fluorobutyl]-6-(3,5-difluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   1-90:    6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-{[(2S,4S)-4-fluoropyrrolidin-2-yl]methyl}-N-methylquinoline-4-carboxamide;-   1-91:    6-(3-fluoro-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide.

In some embodiments, provided herein is a pharmaceutically acceptablesalt of a compound that is described in Table 1.

TABLE 2

Cpd No. R R⁹ R¹⁰ R¹¹ R¹² R¹³ 2-1

CH₃ 3-Cl 5-CH₃ 3′-OH H 2-2

CH₃ 3-OH H 3′-OH H 2-3

CH₃ 3-Cl 5-CH₃ 3′-OH 6′-F 2-4

CH₃ 3-Cl 5-CH₃ 3′-OH 5′-CN 2-5

CH₃ 3-CH₃ 5-CH₃ 3′-OH 5′-CN 2-6

CH₃ 3-Cl 5-CH₃ 3′-OH 5′-CN 2-7

CH₃ 3-F 5-CH₃ 3′-OH 5′-CN 2-8

CH₃ 3-(pyrazol-1-yl) H 3′-OH H 2-9

CH₃ 3-F 5-F 3′-OH H 2-10

CH₃ 3-CH₂CH₂OH H 3′-CN 5′-F 2-11

CH₃ H H 3′-CN 5′-F 2-12

CH₃ 3-MeO H 3′-CN 5′-F 2-13

CH₃ 3-F H 3′-CN 5′-F 2-14

CH₃ 3-CH₂NHAc H 3′-CN 5′-F 2-15

CH₃ 3-CN H 3′-CN 5′-F 2-16

CH₃ 3-F 5-F 3′-CN 5′-F 2-17

CH₃ 3-CH₃ 5-F 3′-CN 5′-F 2-18

CH₃ 3-OMe 5-F 3′-CN 5′-F 2-19

CH₃ 3-F 5-F 3′-CN H 2-20

CH₃ 3-CH₂CO₂H H 3′-OH H 2-21

CH₃ 3-CH₂CO₂Me H 3′-OH H 2-22

CH₃ 3-CH₂—CH₂CO₂H H 3′-OH H 2-23

CH₃ 3-CH₂—CH₂CO₂Me H 3′-OH H 2-24

CH₃ 3-CH₃ 5-F 3′-CONH₂ 5′-F

Compounds in Table 2 are named:

-   2-1:    3-(3-chloro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   2-2:    3,6-bis(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   2-3:    3-(3-chloro-5-methylphenyl)-6-(2-fluoro-5-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   2-4:    3-(3-chloro-5-methylphenyl)-6-(3-cyano-5-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   2-5:    N-[(2S)-2-aminobutyl]-6-(3-cyano-5-hydroxyphenyl)-3-(3,5-dimethylphenyl)-N-methyl-1,5-naphthyridine-4-carboxamide;-   2-6:    N-[(2S)-2-aminobutyl]-3-(3-chloro-5-methylphenyl)-6-(3-cyano-5-hydroxyphenyl)-N-methyl-1,5-naphthyridine-4-carboxamide;-   2-7:    N-[(2S)-2-aminobutyl]-6-(3-cyano-5-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-1,5-naphthyridine-4-carboxamide;-   2-8:    6-(3-hydroxyphenyl)-N-methyl-3-[3-(1H-pyrazol-1-yl)phenyl]-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   2-9:    3-(3,5-difluorophenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   2-10:    6-(3-cyano-5-fluorophenyl)-3-[3-(2-hydroxyethyl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   2-11:    6-(3-cyano-5-fluorophenyl)-N-methyl-3-phenyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   2-12:    6-(3-cyano-5-fluorophenyl)-3-(3-methoxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   2-13:    6-(3-cyano-5-fluorophenyl)-3-(3-fluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   2-14:    6-(3-cyano-5-fluorophenyl)-3-[3-(acetamidomethyl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   2-15:    6-(3-cyano-5-fluorophenyl)-3-(3-cyanophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   2-16:    6-(3-cyano-5-fluorophenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   2-17:    6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   2-18:    6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methoxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   2-19:    6-(3-cyanophenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   2-20:    2-{3-[6-(3-hydroxyphenyl)-4-[methyl(pyrrolidin-2-ylmethyl)carbamoyl]-1,5-naphthyridin-3-yl]phenyl}acetic    acid;-   2-21: methyl    2-{3-[6-(3-hydroxyphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}-1,5-naphthyridin-3-yl]phenyl}acetate;-   2-22:    3-{3-[6-(3-hydroxyphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}-1,5-naphthyridin-3-yl]phenyl}propanoic    acid;-   2-23: methyl    3-{3-[6-(3-hydroxyphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}-1,5-naphthyridin-3-yl]phenyl}propanoate;-   2-24:    6-(3-carbamoyl-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide.

In some embodiments, provided herein is a pharmaceutically acceptablesalt of a compound that is described in Table 2.

TABLE 3

Cpd No. R A¹ R^(A) R^(B) 3-1

N H

3-2

N

3-3

N

3-4

N

3-5

N

3-6

N

3-6

N Cl

3-7

N

3-8

CH

3-9

N

3-10

CH

3-11

N

3-12

N

3-13

CH

3-14

CH

3-15

CH

3-16

CH

3-17

CH

3-18

N

3-19

CH

3-20

CH

3-21

CH

3-22

CH

3-33

CH

3-34

CH

3-35

CH

3-36

N

3-37

CH

3-38

CH

3-39

CH

3-40

CH

3-41

CH

3-42

N

3-43

N

3-44

CH

3-45

CH

3-46

CH

3-47

N

3-48

CH

3-49

N

3-50

CH

3-51

CH

3-52

CH

3-53

CH

3-54

CH

3-55

N

3-56

CH

3-57

CH

3-58

CH

3-59

CH

3-60

CH

3-61

CH

3-62

CH

3-64

CH

3-65

CH

3-66

CH

3-67

CH

3-68

CH

3-69

N

3-70

N

3-71

CH

3-72

CH

3-73

CH

3-74

CH

3-75

CH

3-76

N

3-77

CH

3-78

CH

3-79

CH

3-80

CH

3-81

CH

3-82

CH

3-83

CH

3-84

CH

3-85

CH

3-86

CH

3-87

CH

3-88

CH

3-89

CH

3-90

CH

3-91

CH

3-92

CH

3-93

CH

3-94

CH

3-95

CH

3-96

CH

3-97

CH

3-98

CH

3-99

CH

3-100

CH

3-101

CH

3-102

CH

3-103

CH

3-104

CH

3-105

CH

3-106

CH

3-107

CH

Compounds in Table 3 are named:

-   3-1:    6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-2:    3-(3-fluoro-5-methylphenyl)-N-methyl-6-(pyrrolidin-1-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-3:    3-(3-fluoro-5-methylphenyl)-6-(3-hydroxypiperidin-1-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-4:    6-(3-hydroxyphenyl)-N-methyl-3-(pyrrolidin-1-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-5:    6-(3-hydroxyphenyl)-N-methyl-3-(6-methylpyridin-2-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-6:    3-(2,6-dimethylmorpholin-4-yl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-7:    6-(3-cyano-5-fluorophenyl)-N-methyl-3-(prop-1-yn-1-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-8:    6-(5-cyanopyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-9:    6-(3-cyano-5-fluorophenyl)-3-(cyclopent-1-en-1-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-10:    3-(3-fluoro-5-methylphenyl)-N-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-11:    6-(3-hydroxyphenyl)-N-methyl-3-(piperidin-1-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-12:    6-(3-hydroxyphenyl)-N-methyl-3-(morpholin-4-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-13:    6-(6-cyanopyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-14:    6-(4-cyanopyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-15:    6-(2-amino-5-cyanopyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-16:    6-(2-cyanopyridin-4-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-17:    3-[3-(hydroxymethyl)pyrrolidin-1-yl]-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-18:    6-(3-hydroxyphenyl)-N-methyl-3-(prop-1-yn-1-yl)-N-((2S)-pyrrolidin-2-ylmethyl)-1,5-naphthyridine-4-carboxamide;-   3-19:    6-(4-cyanopyrimidin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-20:    3-(cis-2,6-dimethylmorpholin-4-yl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-21:    3-(trans-2,6-dimethylmorpholin-4-yl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-22:    6-(5-cyano-2,4-dimethylpyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-33:    6-(2-carbamoylpyridin-4-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-34:    6-(3-cyano-5-fluorophenyl)-3-(2-fluoro-3,5-dimethylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-35:    6-(3-cyano-5-fluorophenyl)-3-(2,6-dimethylmorpholin-4-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-36:    6-(3-cyano-5-fluorophenyl)-3-(2,6-dimethylmorpholin-4-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-37:    6-[5-cyano-2-(methylamino)pyridin-3-yl]-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-38:    6-[5-cyano-2-(dimethylamino)pyridin-3-yl]-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-39:    6-(5-cyano-2-methylpyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-40:    6-(5-cyanopyridin-3-yl)-3-[3-fluoro-5-(2-hydroxyethyl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-41:    N-[(2S)-2-aminobutyl]-6-[5-cyano-2-(dimethylamino)pyridin-3-yl]-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   3-42:    6-(3-cyano-5-fluorophenyl)-N-methyl-3-[(2R)-2-phenylmorpholin-4-yl]-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-43:    6-(3-cyano-5-fluorophenyl)-N-methyl-3-(3-methylbutyl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-44:    6-(6-carbamoylpyrazin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-45:    6-(3-cyano-5-fluorophenyl)-3-(2,6-dimethylmorpholin-4-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-46:    3-(3-fluoro-5-methylphenyl)-N-methyl-6-[6-(methylcarbamoyl)pyridin-2-yl]-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-47:    6-(3-cyano-5-fluorophenyl)-N-methyl-3-[(2S)-2-phenylmorpholin-4-yl]-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-48:    3-(3-fluoro-5-methylphenyl)-N-methyl-6-(pyridin-3-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-49:    6-(3-cyano-5-fluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-3-(2,2,6,6-tetramethylmorpholin-4-yl)-1,5-naphthyridine-4-carboxamide;-   3-50:    6-(3-carbamoyl-4,5-difluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-51:    6-(6-aminopyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-52:    6-(3-carbamoyl-2,5-difluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-53:    3-(3-fluoro-5-methylphenyl)-6-(6-methoxypyridin-2-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-54:    6-(3-cyano-5-fluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-3-[5-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]-1,5-naphthyridine-4-carboxamide;-   3-55:    6-(3-cyano-5-fluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-3-[5-(trifluoromethyl)-2,3-dihydro-1H-isoindol-2-yl]-1,5-naphthyridine-4-carboxamide;-   3-56:    6-(5-cyano-2-hydroxypyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-57:    6-(6-carbamoyl-3-methylpyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-58:    6-(5-carbamoylpyridin-3-yl)-3-[3-fluoro-5-(2-hydroxyethyl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-59:    3-(3-fluoro-5-methylphenyl)-6-(5-fluoropyridin-3-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-60:    3-(3-fluoro-5-methylphenyl)-6-(1H-indol-6-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-61:    3-(3-fluoro-5-methylphenyl)-6-(1H-indol-4-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-62:    6-(2-amino-5-fluoropyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-64:    6-(3-carbamoyl-5-fluorophenyl)-3-[(cis)-2,6-dimethylmorpholin-4-yl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-65:    3-(3-fluoro-5-methylphenyl)-N-methyl-6-(4-methylpyridin-3-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-66:    3-(3-fluoro-5-methylphenyl)-N-methyl-6-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-67:    N-[(2S)-2-aminobutyl]-6-(6-carbamoylpyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   3-68:    6-(5-chloropyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-69:    3-{3-azabicyclo[3.1.0]hexan-3-yl}-6-(3-cyano-5-fluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-70:    6-(3-cyano-5-fluorophenyl)-N-methyl-3-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-71:    3-(3-fluoro-5-methylphenyl)-N-methyl-6-(pyrimidin-5-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-72:    6-[4-cyano-6-(morpholin-4-yl)pyridin-2-yl]-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-73:    3-(3-fluoro-5-methylphenyl)-N-methyl-6-[2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-1,3-benzodiazol-4-yl]-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-74:    3-(3-fluoro-5-methylphenyl)-6-(4-fluoropyridin-3-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-75:    6-(4-chloropyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-76:    6-(3-cyano-5-fluorophenyl)-3-(3,3-difluoropyrrolidin-1-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;-   3-77:    6-(6-carbamoylpyridin-2-yl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-78:    6-(6-carbamoyl-3-fluoropyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-79:    6-(6-carbamoyl-3-methylpyridin-2-yl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-80:    6-(4-carbamoylpyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-81:    3-(3-fluoro-5-methylphenyl)-6-(5-methoxypyridin-3-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-82:    3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-6-(6-sulfamoylpyridin-2-yl)quinoline-4-carboxamide;-   3-83:    3-(3-fluoro-5-methylphenyl)-N-methyl-6-(5-methylpyridin-3-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-84:    3-(3-fluoro-5-methylphenyl)-6-[5-(hydroxymethyl)pyridin-3-yl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-85:    3-(3-chloro-5-methylphenyl)-6-(5-hydroxypyridin-3-yl)-N,7-dimethyl-N-[(2S)-pyrrolidin-2-ylmethyl]-3,4-dihydroquinazoline-4-carboxamide;-   3-86:    6-[5-(difluoromethoxy)pyridin-3-yl]-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-87: ethyl    (2S)-2-({1-[6-(6-carbamoylpyridin-2-yl)-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate;-   3-88:    6-(6-carbamoylpyridin-2-yl)-3-(3-chloro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-89:    6-(6-carbamoyl-3-fluoropyridin-2-yl)-3-(3-chloro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-90:    6-(6-carbamoyl-3-methylpyridin-2-yl)-3-(3-chloro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-91:    6-(6-carbamoyl-3-chloropyridin-2-yl)-3-(3-chloro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-92:    N-[(2S)-azetidin-2-ylmethyl]-6-(6-carbamoylpyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   3-93:    N-[(2S)-azetidin-2-ylmethyl]-6-(6-carbamoyl-3-fluoropyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   3-94:    N-[(2S)-azetidin-2-ylmethyl]-6-(6-carbamoyl-3-methylpyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   3-95:    N-[(2S)-azetidin-2-ylmethyl]-6-(6-carbamoyl-3-chloropyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;-   3-96:    6-(6-carbamoylpyridin-2-yl)-3-(3,5-dichlorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-97:    6-(6-carbamoyl-3-fluoropyridin-2-yl)-3-(3,5-dichlorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-98:    6-(6-carbamoyl-3-methylpyridin-2-yl)-3-(3,5-dichlorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-99:    6-(6-carbamoyl-3-chloropyridin-2-yl)-3-(3,5-dichlorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-100:    N-[(2S)-azetidin-2-ylmethyl]-6-(6-carbamoylpyridin-2-yl)-3-(3,5-dichlorophenyl)-N-methylquinoline-4-carboxamide;-   3-101:    N-[(2S)-azetidin-2-ylmethyl]-6-(6-carbamoyl-3-fluoropyridin-2-yl)-3-(3,5-dichlorophenyl)-N-methylquinoline-4-carboxamide;-   3-102:    N-[(2S)-azetidin-2-ylmethyl]-6-(6-carbamoyl-3-methylpyridin-2-yl)-3-(3,5-dichlorophenyl)-N-methylquinoline-4-carboxamide;-   3-103:    N-[(2S)-azetidin-2-ylmethyl]-6-(6-carbamoyl-3-chloropyridin-2-yl)-3-(3,5-dichlorophenyl)-N-methylquinoline-4-carboxamide;-   3-104:    6-(6-carbamoylpyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-{[(2S)-1-methylpyrrolidin-2-yl]methyl}quinoline-4-carboxamide;-   3-105:    3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-6-[5-(trifluoromethyl)pyridin-3-yl]quinoline-4-carboxamide;-   3-106:    3-(3-fluoro-5-methylphenyl)-N-methyl-6-(4-oxo-3,4-dihydro-2H-1,3-benzoxazin-6-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;-   3-107:    6-(3,5-difluoro-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide.

In some embodiments, provided herein is a pharmaceutically acceptablesalt of a compound that is described in Table 3.

In one aspect, compounds described herein are in the form ofpharmaceutically acceptable salts. As well, active metabolites of thesecompounds having the same type of activity are included in the scope ofthe present disclosure. In addition, the compounds described herein canexist in unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein.

“Pharmaceutically acceptable,” as used herein, refers a material, suchas a carrier or diluent, which does not abrogate the biological activityor properties of the compound, and is relatively nontoxic, i.e., thematerial is administered to an individual without causing undesirablebiological effects or interacting in a deleterious manner with any ofthe components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a form of atherapeutically active agent that consists of a cationic form of thetherapeutically active agent in combination with a suitable anion, or inalternative embodiments, an anionic form of the therapeutically activeagent in combination with a suitable cation. Handbook of PharmaceuticalSalts: Properties, Selection and Use. International Union of Pure andApplied Chemistry, Wiley-VCH 2002. S. M. Berge, L. D. Bighley, D. C.Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth,editors, Handbook of Pharmaceutical Salts: Properties, Selection andUse, Weinheim/Zirich:Wiley-VCH/VHCA, 2002. Pharmaceutical saltstypically are more soluble and more rapidly soluble in stomach andintestinal juices than non-ionic species and so are useful in soliddosage forms. Furthermore, because their solubility often is a functionof pH, selective dissolution in one or another part of the digestivetract is possible and this capability can be manipulated as one aspectof delayed and sustained release behaviours. Also, because thesalt-forming molecule can be in equilibrium with a neutral form, passagethrough biological membranes can be adjusted.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound of Formula (I) with an acid. In some embodiments,the compound of Formula (I) (i.e. free base form) is basic and isreacted with an organic acid or an inorganic acid. Inorganic acidsinclude, but are not limited to, hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.Organic acids include, but are not limited to, 1-hydroxy-2-naphthoicacid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid;2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid;acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L);benzenesulfonic acid; benzoic acid; camphoric acid (+);camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid(hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamicacid; citric acid; cyclamic acid; dodecylsulfuric acid;ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaricacid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconicacid (D); glucuronic acid (D); glutamic acid; glutaric acid;glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid;lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid(−L); malonic acid; mandelic acid (DL); methanesulfonic acid;naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinicacid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoricacid; proprionic acid; pyroglutamic acid (−L); salicylic acid; sebacicacid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L);thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

In some embodiments, a compound of Formula (I) is prepared as a chloridesalt, sulfate salt, bromide salt, mesylate salt, maleate salt, citratesalt or phosphate salt.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound of Formula (I) with a base. In some embodiments, thecompound of Formula (I) is acidic and is reacted with a base. In suchsituations, an acidic proton of the compound of Formula (I) is replacedby a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, oran aluminum ion. In some cases, compounds described herein coordinatewith an organic base, such as, but not limited to, ethanolamine,diethanolamine, triethanolamine, tromethamine, meglumine,N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. Inother cases, compounds described herein form salts with amino acids suchas, but not limited to, arginine, lysine, and the like. Acceptableinorganic bases used to form salts with compounds that include an acidicproton, include, but are not limited to, aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium hydroxide, lithium hydroxide, and the like. In some embodiments,the compounds provided herein are prepared as a sodium salt, calciumsalt, potassium salt, magnesium salt, meglumine salt, N-methylglucaminesalt or ammonium salt.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms. In someembodiments, solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and are formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, and the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.Solvates of compounds described herein are conveniently prepared orformed during the processes described herein. In addition, the compoundsprovided herein optionally exist in unsolvated as well as solvatedforms.

The methods and formulations described herein include the use ofN-oxides (if appropriate), or pharmaceutically acceptable salts ofcompounds having the structure of Formula (I), as well as activemetabolites of these compounds having the same type of activity.

In some embodiments, sites on the organic radicals (e.g. alkyl groups,aromatic rings) of compounds of Formula (I) are susceptible to variousmetabolic reactions. Incorporation of appropriate substituents on theorganic radicals will reduce, minimize or eliminate this metabolicpathway. In specific embodiments, the appropriate substituent todecrease or eliminate the susceptibility of the aromatic ring tometabolic reactions is, by way of example only, a halogen, deuterium, analkyl group, a haloalkyl group, or a deuteroalkyl group.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by another other means,including, but not limited to, the use of chromophores or fluorescentmoieties, bioluminescent labels, or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine,phosphorus, such as, for example, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S,¹⁸F, ³⁶Cl, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ³²P and ³³P. In one aspect,isotopically-labeled compounds described herein, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. In oneaspect, substitution with isotopes such as deuterium affords certaintherapeutic advantages resulting from greater metabolic stability, suchas, for example, increased in vivo half-life or reduced dosagerequirements.

In some embodiments, the compounds of Formula (I) possess one or morestereocenters and each stereocenter exists independently in either the Ror S configuration. In some embodiments, the compound of Formula (I)exists in the R configuration. In some embodiments, the compound ofFormula (I) exists in the S configuration. The compounds presentedherein include all diastereomeric, individual enantiomers, atropisomers,and epimeric forms as well as the appropriate mixtures thereof. Thecompounds and methods provided herein include all cis, trans, syn, anti,entgegen (E), and zusammen (Z) isomers as well as the appropriatemixtures thereof.

Individual stereoisomers are obtained, if desired, by methods such as,stereoselective synthesis and/or the separation of stereoisomers bychiral chromatographic columns or the separation of diastereomers byeither non-chiral or chiral chromatographic columns or crystallizationand recrystallization in a proper solvent or a mixture of solvents. Incertain embodiments, compounds of Formula (I) are prepared as theirindividual stereoisomers by reacting a racemic mixture of the compoundwith an optically active resolving agent to form a pair ofdiastereoisomeric compounds/salts, separating the diastereomers andrecovering the optically pure individual enantiomers. In someembodiments, resolution of individual enantiomers is carried out usingcovalent diastereomeric derivatives of the compounds described herein.In another embodiment, diastereomers are separated byseparation/resolution techniques based upon differences in solubility.In other embodiments, separation of steroisomers is performed bychromatography or by the forming diastereomeric salts and separation byrecrystallization, or chromatography, or any combination thereof. JeanJacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates andResolutions”, John Wiley And Sons, Inc., 1981. In some embodiments,stereoisomers are obtained by stereoselective synthesis.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they are easier to administer than the parent drug. Theyare, for instance, bioavailable by oral administration whereas theparent is not. Further or alternatively, the prodrug also has improvedsolubility in pharmaceutical compositions over the parent drug. In someembodiments, the design of a prodrug increases the effective watersolubility. An example, without limitation, of a prodrug is a compounddescribed herein, which is administered as an ester (the “prodrug”) butthen is metabolically hydrolyzed to provide the active entity. A furtherexample of a prodrug is a short peptide (polyaminoacid) bonded to anacid group where the peptide is metabolized to reveal the active moiety.In certain embodiments, upon in vivo administration, a prodrug ischemically converted to the biologically, pharmaceutically ortherapeutically active form of the compound. In certain embodiments, aprodrug is enzymatically metabolized by one or more steps or processesto the biologically, pharmaceutically or therapeutically active form ofthe compound.

Prodrugs of the compounds described herein include, but are not limitedto, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives,N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternaryderivatives of tertiary amines, N-Mannich bases, Schiff bases, aminoacid conjugates, phosphate esters, and sulfonate esters. See for exampleDesign of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method inEnzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396;Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of DrugDesign and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991,Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review,1992, 8, 1-38, each of which is incorporated herein by reference. Insome embodiments, a hydroxyl group in the compounds disclosed herein isused to form a prodrug, wherein the hydroxyl group is incorporated intoan acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, arylester, phosphate ester, sugar ester, ether, and the like. In someembodiments, a hydroxyl group in the compounds disclosed herein is aprodrug wherein the hydroxyl is then metabolized in vivo to provide acarboxylic acid group. In some embodiments, a carboxyl group is used toprovide an ester or amide (i.e. the prodrug), which is then metabolizedin vivo to provide a carboxylic acid group. In some embodiments,compounds described herein are prepared as alkyl ester prodrugs.

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound of Formula (I) as set forthherein are included within the scope of the claims. In some cases, someof the herein-described compounds is a prodrug for another derivative oractive compound.

In some embodiments, any one of the hydroxyl group(s), amino group(s)and/or carboxylic acid group(s) are functionalized in a suitable mannerto provide a prodrug moiety. In some embodiments, the prodrug moiety isas described above.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Metabolites of the compounds disclosed herein areoptionally identified either by administration of compounds to a hostand analysis of tissue samples from the host, or by incubation ofcompounds with hepatic cells in vitro and analysis of the resultingcompounds.

Synthesis of Compounds

Compounds of Formula (I) described herein are synthesized using standardsynthetic techniques or using methods known in the art in combinationwith methods described herein.

Unless otherwise indicated, conventional methods of mass spectroscopy,NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniquesand pharmacology are employed.

Compounds are prepared using standard organic chemistry techniques suchas those described in, for example, March's Advanced Organic Chemistry,6^(th) Edition, John Wiley and Sons, Inc. Alternative reactionconditions for the synthetic transformations described herein may beemployed such as variation of solvent, reaction temperature, reactiontime, as well as different chemical reagents and other reactionconditions.

In some embodiments, compounds described herein are prepared asdescribed in Scheme A.

Compound I is reacted with an alcohol such as methanol in the presenceof a strong acid such as sulfuric acid to form ester and is followed byan organometallic coupling reaction such as Suzuki-Miyaura reaction withR²B(OH)₂ leads to formation of compound II. Formation of the triflate oncompound II, followed by another organometallic coupling reaction suchas Suzuki-Miyaura reaction with R¹B(OH)₂ yields compound III. Hydrolysisof the ester under basic condition gives rise to the acid which iscoupled with the mono-protected diamine (RR⁹NH, where R containing aprotected amino group), in the presence of a coupling reagent such asHATU, and subsequent removal of all protecting groups using appropriatedeprotection methods such as acid, yields the compound IV.

In some other embodiments, the intermediate III is synthesized asoutlined in Scheme B.

Compound Ia is reacted with an alcohol such as methanol in the presenceof a strong acid such as sulfuric acid to form ester and is followed byformation of the triflate to produce V. Two consecutive but selectiveSuzuki-Miyaura reactions with R¹B(OH)₂ and R²B(OH)₂ leads to formationof compound III.

Intermediate IIIb is synthesized as outlined in Scheme C

Compound Ib is reacted with an alcohol such as methanol in the presenceof a strong acid such as sulfuric acid to form ester and followed byformation of the triflate to produce Vb. Two consecutive but selectiveSuzuki-Miyaura reactions with R²B(OH)₂ and then R¹B(OH)₂ leads toformation of compound IIIb. Following the same route in Scheme A fromIII to IV, the final desired compounds are obtained.

In some embodiments, compounds described herein are prepared asdescribed in Scheme D using Ib as the starting material.

Compound Ib is coupled with the mono-protected diamine (RR⁹NH, where Rcontaining a protected amino group), in the presence of a couplingreagent such as HATU, followed by formation of the triflate to produceVI. Two consecutive but selective Suzuki-Miyaura reactions with R²B(OH)₂and then R¹B(OH)₂ or other similar coupling reactions and subsequentremoval of all protecting groups using appropriate deprotection methodssuch as acid, yield the compound IV. Alternatively, R¹ or R² is asubstituted amino group, where R² is introduced by heating of VI with anamine in step c, and R¹ is introduced by Buchwald-Hartwig amination ofchloride with an amine in step d.

In some embodiments, compounds described herein are prepared asdescribed in Scheme E using V as the starting material.

Compound V which is described in the previous Scheme II undergoes aselective Suzuki-Miyaura reaction to obtain compound VII. The ester ofVII is removed by acid or base, followed by a coupling reaction with theamine RR₉NH to form amide compound VIII. The boronic ester VIV is formedwhen VIII is reacted with (pinB)₂ in the presence of a palladiumcatalyst such as Pd₂dba₃ with a ligand such as x-Phos. A Suzuki-Miyaurareaction with a halogen of triflate of R₂, followed by deprotectionyields the desired compound IV.

In some embodiments, the compounds obtained from the above mentionedmethods are prepared as racemic or diastereomic mixtures. In some otherembodiments, racemic mixtures of the compounds are separated to obtainoptically pure (or optically enriched) isomers by the use of commonchiral separation methods such as chiral HPLC, chiral supercriticalfluid chromatographic system (SFC), simulated moving bed chromatography(SMB), and the like.

In some other embodiments, diastereomic mixtures of the compounds areseparated to obtain optically pure (or optically enriched) isomers bythe use of crystallization methods or common non-chiral chromatographymethods such as silica gel chromatography or chiral chromatographymethods such as chiral HPLC, chiral supercritical fluid chromatographicsystem (SFC), simulated moving bed chromatography (SMB), and the like.

In some embodiments, compounds described herein are synthesized asoutlined in the Examples.

Certain Terminology

Unless otherwise stated, the following terms used in this applicationhave the definitions given below. The use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting. The section headings used herein are for organizationalpurposes only and are not to be construed as limiting the subject matterdescribed.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). By way ofexample only, a group designated as “C₁-C₆” indicates that there are oneto six carbon atoms in the moiety, i.e. groups containing 1 carbon atom,2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl group, i.e., the alkyl group is selected from amongmethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andt-butyl.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroup is branched or straight chain. In some embodiments, the “alkyl”group has 1 to 10 carbon atoms, i.e. a C₁-C₁₀alkyl. Whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl groupconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 10 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated. In some embodiments, an alkyl is a C₁-C₆alkyl. In one aspectthe alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, or t-butyl. Typical alkyl groups include, but are in no waylimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

An “alkylene” group refers refers to a divalent alkyl radical. Any ofthe above mentioned monovalent alkyl groups may be an alkylene byabstraction of a second hydrogen atom from the alkyl. In someembodiments, an alkelene is a C₁-C₆alkylene. In other embodiments, analkylene is a C₁-C₄alkylene. Typical alkylene groups include, but arenot limited to, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and thelike. In some embodiments, an alkylene is —CH₂—.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where x is0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

An “hydroxyalkyl” refers to an alkyl in which one hydrogen atom isreplaced by a hydroxyl. In some embodiments, a hydroxyalkyl is aC₁-C₄hydroxyalkyl. Typical hydroxyalkyl groups include, but are notlimited to, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH, and thelike.

An “aminoalkyl” refers to an alkyl in which one hydrogen atom isreplaced by an amino. In some embodiments, aminoalkyl is aC₁-C₄aminoalkyl. Typical aminoalkyl groups include, but are not limitedto, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂, and the like.

The term “alkenyl” refers to a type of alkyl group in which at least onecarbon-carbon double bond is present. In one embodiment, an alkenylgroup has the formula —C(R)═CR₂, wherein R refers to the remainingportions of the alkenyl group, which may be the same or different. Insome embodiments, R is H or an alkyl. In some embodiments, an alkenyl isselected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl,pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenylgroup include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃, —C(CH₃)═CHCH₃, and—CH₂CH═CH₂.

The term “alkynyl” refers to a type of alkyl group in which at least onecarbon-carbon triple bond is present. In one embodiment, an alkenylgroup has the formula —C≡C—R, wherein R refers to the remaining portionsof the alkynyl group. In some embodiments, R is H or an alkyl. In someembodiments, an alkynyl is selected from ethynyl, propynyl, butynyl,pentynyl, hexynyl, and the like. Non-limiting examples of an alkynylgroup include —C≡CH, —C≡CCH₃—C≡CCH₂CH₃, —CH₂C≡CH.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-, sulfur, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In one aspect, a heteroalkyl is aC₁-C₆heteroalkyl.

The term “aromatic” refers to a planar ring having a delocalizedit-electron system containing 4n+2 π electrons, where n is an integer.The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g.,phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”)groups (e.g., pyridine). The term includes monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups.

The term “carbocyclic” or “carbocycle” refers to a ring or ring systemwhere the atoms forming the backbone of the ring are all carbon atoms.The term thus distinguishes carbocyclic from “heterocyclic” rings or“heterocycles” in which the ring backbone contains at least one atomwhich is different from carbon. In some embodiments, at least one of thetwo rings of a bicyclic carbocycle is aromatic. In some embodiments,both rings of a bicyclic carbocycle are aromatic. Carbocycles includearyls and cycloalkyls.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. In one aspect, aryl isphenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In someembodiments, an aryl is a phenyl, naphthyl, indanyl, indenyl, ortetrahyodronaphthyl. In some embodiments, an aryl is a C₆-C₁₀aryl.Depending on the structure, an aryl group is a monoradical or adiradical (i.e., an arylene group).

The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic,non-aromatic radical, wherein each of the atoms forming the ring (i.e.skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls arespirocyclic or bridged compounds. In some embodiments, cycloalkyls areoptionally fused with an aromatic ring, and the point of attachment isat a carbon that is not an aromatic ring carbon atom. Cycloalkyl groupsinclude groups having from 3 to 10 ring atoms. In some embodiments,cycloalkyl groups are selected from among cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Insome embodiments, a cycloalkyl is a C₃-C₆cycloalkyl.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, orbromo.

The term “fluoroalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is aC₁-C₆fluoroalkyl.

The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings(also known as heteroaryls) and heterocycloalkyl rings containing one tofour heteroatoms in the ring(s), where each heteroatom in the ring(s) isselected from O, S and N, wherein each heterocyclic group has from 3 to10 atoms in its ring system, and with the proviso that any ring does notcontain two adjacent O or S atoms. Non-aromatic heterocyclic groups(also known as heterocycloalkyls) include rings having 3 to 10 atoms inits ring system and aromatic heterocyclic groups include rings having 5to 10 atoms in its ring system. The heterocyclic groups includebenzo-fused ring systems. Examples of non-aromatic heterocyclic groupsare pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,oxazolidinonyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl,indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl,3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl,isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl,1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups are either C-attached (or C-linked)or N-attached where such is possible. For instance, a group derived frompyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole includesimidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems. Non-aromatic heterocycles areoptionally substituted with one or two oxo (═O) moieties, such aspyrrolidin-2-one. In some embodiments, at least one of the two rings ofa bicyclic heterocycle is aromatic. In some embodiments, both rings of abicyclic heterocycle are aromatic.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groupsinclude monocyclic heteroaryls and bicyclcic heteroaryls. Monocyclicheteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine,indole, benzofuran, benzothiophene, indazole, benzimidazole, purine,quinolizine, quinoline, isoquinoline, cinnoline, phthalazine,quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In someembodiments, a heteroaryl contains 0-4 N atoms in the ring. In someembodiments, a heteroaryl contains 1-4 N atoms in the ring. In someembodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 Satoms in the ring. In some embodiments, a heteroaryl contains 1-4 Natoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments,heteroaryl is a C₁-C₉heteroaryl. In some embodiments, monocyclicheteroaryl is a C₁-C₅heteroaryl. In some embodiments, monocyclicheteroaryl is a 5-membered or 6-membered heteroaryl. In someembodiments, bicyclic heteroaryl is a C₆-C₉heteroaryl.

A “heterocycloalkyl” group refers to a cycloalkyl group that includes atleast one heteroatom selected from nitrogen, oxygen and sulfur. In someembodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. Insome embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl,pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl,imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heterocycloalkylalso includes all ring forms of the carbohydrates, including but notlimited to the monosaccharides, the disaccharides and theoligosaccharides. In one aspect, a heterocycloalkyl is aC₂-C₁₀heterocycloalkyl. In another aspect, a heterocycloalkyl is aC₄-C₁₀heterocycloalkyl. In some embodiments, a heterocycloalkyl contains0-2 N atoms in the ring. In some embodiments, a heterocycloalkylcontains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure. In one aspect, when a group describedherein is a bond, the referenced group is absent thereby allowing a bondto be formed between the remaining identified groups.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The term “optionally substituted” or “substituted” means that thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from halogen, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some other embodiments, optional substituents are independentlyselected from halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H,—CO₂(C₁-C₄alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₄alkyl), —C(═O)N(C₁-C₄alkyl)₂,—S(═O)₂NH₂, —S(═O)₂NH(C₁-C₄alkyl), —S(═O)₂N(C₁-C₄alkyl)₂, C₁-C₄alkyl,C₃-C₆cycloalkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, —SC₁-C₄alkyl, —S(═O)C₁-C₄alkyl, and—S(═O)₂C₁-C₄alkyl. In some embodiments, optional substituents areindependently selected from halogen, —CN, —NH₂, —OH, —NH(CH₃), —N(CH₃)₂,—CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃. In some embodiments, substitutedgroups are substituted with one or two of the preceding groups. In someembodiments, an optional substituent on an aliphatic carbon atom(acyclic or cyclic) includes oxo (═O).

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “modulate” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator” as used herein, refers to a molecule that interactswith a target either directly or indirectly. The interactions include,but are not limited to, the interactions of an agonist, partial agonist,an inverse agonist, antagonist, degrader, or combinations thereof. Insome embodiments, a modulator is an agonist.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein. In some embodiments, the compounds andcompositions described herein are administered orally.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered, which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result includesreduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case is optionallydetermined using techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and a co-agent, are both administered to apatient simultaneously in the form of a single entity or dosage. Theterm “non-fixed combination” means that the active ingredients, e.g. acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and a co-agent, are administered to a patient as separate entitieseither simultaneously, concurrently or sequentially with no specificintervening time limits, wherein such administration provides effectivelevels of the two compounds in the body of the patient. The latter alsoapplies to cocktail therapy, e.g. the administration of three or moreactive ingredients.

The terms “article of manufacture” and “kit” are used as synonyms.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one aspect, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Pharmaceutical Compositions

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that are used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein is found, for example, inRemington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton,Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999),herein incorporated by reference for such disclosure.

In some embodiments, the compounds described herein are administeredeither alone or in combination with pharmaceutically acceptablecarriers, excipients or diluents, in a pharmaceutical composition.Administration of the compounds and compositions described herein can beeffected by any method that enables delivery of the compounds to thesite of action. These methods include, though are not limited todelivery via enteral routes (including oral, gastric or duodenal feedingtube, rectal suppository and rectal enema), parenteral routes (injectionor infusion, including intraarterial, intracardiac, intradermal,intraduodenal, intramedullary, intramuscular, intraosseous,intraperitoneal, intrathecal, intravascular, intravenous, intravitreal,epidural and subcutaneous), inhalational, transdermal, transmucosal,sublingual, buccal and topical (including epicutaneous, dermal, enema,eye drops, ear drops, intranasal, vaginal) administration, although themost suitable route may depend upon for example the condition anddisorder of the recipient. By way of example only, compounds describedherein can be administered locally to the area in need of treatment, byfor example, local infusion during surgery, topical application such ascreams or ointments, injection, catheter, or implant. The administrationcan also be by direct injection at the site of a diseased tissue ororgan.

In some embodiments, pharmaceutical compositions suitable for oraladministration are presented as discrete units such as capsules, cachetsor tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. In some embodiments, theactive ingredient is presented as a bolus, electuary or paste.

Pharmaceutical compositions which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. In some embodiments, the tabletsare coated or scored and are formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In some embodiments, stabilizers are added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or Dragee coatings for identification or to characterizedifferent combinations of active compound doses.

In some embodiments, pharmaceutical compositions are formulated forparenteral administration by injection, e.g., by bolus injection orcontinuous infusion. Formulations for injection may be presented in unitdosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. The compositions may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored inpowder form or in a freeze-dried (lyophilized) condition requiring onlythe addition of the sterile liquid carrier, for example, saline orsterile pyrogen-free water, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets of the kind previously described.

Pharmaceutical compositions for parenteral administration includeaqueous and non-aqueous (oily) sterile injection solutions of the activecompounds which may contain antioxidants, buffers, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers or agents which increase the solubility ofthe compounds to allow for the preparation of highly concentratedsolutions.

Pharmaceutical compositions may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds may beformulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

Pharmaceutical compositions may be administered topically, that is bynon-systemic administration. This includes the application of a compoundof the present invention externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Pharmaceutical compositions suitable for topical administration includeliquid or semi-liquid preparations suitable for penetration through theskin to the site of inflammation such as gels, liniments, lotions,creams, ointments or pastes, and drops suitable for administration tothe eye, ear or nose. The active ingredient may comprise, for topicaladministration, from 0.001% to 10% w/w, for instance from 1% to 2% byweight of the formulation.

Pharmaceutical compositions for administration by inhalation areconveniently delivered from an insufflator, nebulizer pressurized packsor other convenient means of delivering an aerosol spray. Pressurizedpacks may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, pharmaceuticalpreparations may take the form of a dry powder composition, for examplea powder mix of the compound and a suitable powder base such as lactoseor starch. The powder composition may be presented in unit dosage form,in for example, capsules, cartridges, gelatin or blister packs fromwhich the powder may be administered with the aid of an inhalator orinsufflator.

It should be understood that in addition to the ingredients particularlymentioned above, the compounds and compositions described herein mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents.

Methods of Dosing and Treatment Regimens

In one embodiment, the compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, are used in the preparation of medicaments forthe treatment of diseases or conditions in a mammal that would benefitfrom modulation of somatostatin activity. Methods for treating any ofthe diseases or conditions described herein in a mammal in need of suchtreatment, involves administration of pharmaceutical compositions thatinclude at least one compound of Formula (I) or a pharmaceuticallyacceptable salt, active metabolite, prodrug, or pharmaceuticallyacceptable solvate thereof, in therapeutically effective amounts to saidmammal.

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest at leastone of the symptoms of the disease or condition. Amounts effective forthis use depend on the severity and course of the disease or condition,previous therapy, the patient's health status, weight, and response tothe drugs, and the judgment of the treating physician. Therapeuticallyeffective amounts are optionally determined by methods including, butnot limited to, a dose escalation and/or dose ranging clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in patients, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician. In one aspect, prophylactic treatments include administeringto a mammal, who previously experienced at least one symptom of thedisease being treated and is currently in remission, a pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, in order to prevent a return of the symptoms ofthe disease or condition.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the patient requires intermittent treatment on a long-termbasis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but nevertheless is determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated.

In general, however, doses employed for adult human treatment aretypically in the range of 0.01 mg-2000 mg per day. In one embodiment,the desired dose is conveniently presented in a single dose or individed doses administered simultaneously or at appropriate intervals,for example as two, three, four or more sub-doses per day.

In one embodiment, the daily dosages appropriate for the compound ofFormula (I), or a pharmaceutically acceptable salt thereof, describedherein are from about 0.01 to about 50 mg/kg per body weight. In someembodiments, the daily dosage or the amount of active in the dosage formare lower or higher than the ranges indicated herein, based on a numberof variables in regard to an individual treatment regime. In variousembodiments, the daily and unit dosages are altered depending on anumber of variables including, but not limited to, the activity of thecompound used, the disease or condition to be treated, the mode ofadministration, the requirements of the individual subject, the severityof the disease or condition being treated, and the judgment of thepractitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ and the ED₅₀. The dose ratio between the toxic andtherapeutic effects is the therapeutic index and it is expressed as theratio between LD₅₀ and ED₅₀. In certain embodiments, the data obtainedfrom cell culture assays and animal studies are used in formulating thetherapeutically effective daily dosage range and/or the therapeuticallyeffective unit dosage amount for use in mammals, including humans. Insome embodiments, the daily dosage amount of the compounds describedherein lies within a range of circulating concentrations that includethe ED₅₀ with minimal toxicity. In certain embodiments, the daily dosagerange and/or the unit dosage amount varies within this range dependingupon the dosage form employed and the route of administration utilized.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound of Formula (I), or apharmaceutically acceptable salt thereof, is: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by injection to the mammal; and/or (e) administeredtopically to the mammal; and/or (f) administered non-systemically orlocally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce a day; or (ii) the compound is administered to the mammal multipletimes over the span of one day.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

Combination Treatments

In certain instances, it is appropriate to administer at least onecompound of Formula (I), or a pharmaceutically acceptable salt thereof,in combination with one or more other therapeutic agents.

In one embodiment, the therapeutic effectiveness of one of the compoundsdescribed herein is enhanced by administration of an adjuvant (i.e., byitself the adjuvant has minimal therapeutic benefit, but in combinationwith another therapeutic agent, the overall therapeutic benefit to thepatient is enhanced). Or, in some embodiments, the benefit experiencedby a patient is increased by administering one of the compoundsdescribed herein with another agent (which also includes a therapeuticregimen) that also has therapeutic benefit.

In one specific embodiment, a compound of Formula (I), or apharmaceutically acceptable salt thereof, is co-administered with asecond therapeutic agent, wherein the compound of Formula (I), or apharmaceutically acceptable salt thereof, and the second therapeuticagent modulate different aspects of the disease, disorder or conditionbeing treated, thereby providing a greater overall benefit thanadministration of either therapeutic agent alone.

In any case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient is simply beadditive of the two therapeutic agents or the patient experiences asynergistic benefit.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more other therapeutic agents, the compoundprovided herein is administered either simultaneously with the one ormore other therapeutic agents, or sequentially.

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills).

The compounds of Formula (I), or a pharmaceutically acceptable saltthereof, as well as combination therapies, are administered before,during or after the occurrence of a disease or condition, and the timingof administering the composition containing a compound varies. Thus, inone embodiment, the compounds described herein are used as aprophylactic and are administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. In another embodiment, thecompounds and compositions are administered to a subject during or assoon as possible after the onset of the symptoms. In specificembodiments, a compound described herein is administered as soon as ispracticable after the onset of a disease or condition is detected orsuspected, and for a length of time necessary for the treatment of thedisease. In some embodiments, the length required for treatment varies,and the treatment length is adjusted to suit the specific needs of eachsubject.

EXAMPLES Abbreviations

ABCN: 1,1′-azobis(cyclohexanecarbonitrile);BINAP: (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl);DCM: dichloromethane;EtOAc: ethyl acetate;HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate;

NBS: N-bromosuccinimide; NCS: N-chlorosuccinimide:

PTS: p-toluene sulfonic acid;Pd (amphos)Cl₂:bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II);Pd₂dba₃: tris(dibenzylideneacetone)dipalladium(0);(pinB)₂: bis(pinacolato)diboron;rt: room temperature;SST: somatostatin;SSTR: somatostatin receptor;TEA: trimethylamine;TFA: trifluoroacetic acid;x-phos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl;hrs: hours;h or hr: hour.

The following examples are provided for illustrative purposes only andnot to limit the scope of the claims provided herein.

Synthesis of Compounds Example 1:3-(3-chloro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide

Step 1-1, preparation of 6-bromo-3-hydroxy-quinoline-carboxylic acidmethyl ester: to 6-bromo-3-hydroxy-quinoline-carboxylic acid (5.0 g,17.5 mmol) in 60 mL methanol was added sulfuric acid (20 ml), and theresulting mixture was stirred at 95° C. for 17 h. The reaction solutionwas diluted with water (400 ml) and resulted precipitates were filteredand redissolved in ethyl acetate and dried with MgSO₄, concentrated togive a solid (1.17 g). MS (M+H)⁺: 282.0

Step 1-2, preparation of6-(3-benzyloxy-phenyl)-3-hydroxy-quinoline-4-carboxylic acid methylester: the solid from Step 1-1 (282.1 mg, 1 mmol) was dissolved indioxane (8 mL) with water (0.8 ml), 3-benzoxylphenyl boronic acid (456.2mg 2.0 mmmol), and K₃PO₄.H₂O (690.9 mg, 3.0 mmol) were added. Themixture was bubbled with N₂ for 10 min, tris(dibenzylideneacetone)dipalladium/tri-tert-butyl phosphonium tetrafluoroborate mixture (moleratio: 1/1.2) (50 mg, 0.039 mmol) was added. The resulting mixture wasstirred at 55° C. for 2 hrs. The reaction mixture was concentrated andpurified by silica gel chromatography to give desired product as brownoil (194 mg). MS (M+H)⁺: 386.2.

Step 1-3, preparation of6-(3-benzyloxy-phenyl)-3-trifluoromethanesulfonyloxy-quinoline-4-carboxylicacid methyl ester: to the oil (194 mg, 0.5 mmol) from Step 1-2 in DCM (4mL), TEA (0.2 ml, 1.4 mmol) was added, followed by addition oftrifluoromethanesulfonic anhydride (Tf₂O, 0.16 ml, 1.0 mmol). Thereaction mixture was stirred at rt for 0.5 hr, additional Tf₂O (0.08 ml)and TEA (0.14 ml) were added. The reaction solution was then stirred foradditional 1 h, concentrated and purified by silica gel chromatographyeluted with hexane and ethyl acetate to afford a brown oil as thedesired product (157 mg). MS (M+1)⁺: 518.3.

Step 1-4, preparation of6-(3-benzyloxy-phenyl)-3-(3-chloro-5-methyl-phenyl)-quinoline-4-carboxylicacid methyl ester: to the dioxane solution (3 mL) of the oil from Step1-3 (157 mg, 0.3 mmol) was added, followed by addition of3-chloro-5-methyl-phenylboronic acid (102 mg, 0.6 mmol), K₂CO₃ (83 mg,0.6 mmol) and water (0.8 mL). The reaction mixture was bubbled with N₂for 5 min and then Pd(amphos)Cl₂ was added and the mixture was stirredat 90° C. for 45 min. The reaction solution was concentrated andpurified by silica gel chromatography eluted with hexane and ethylacetate to afford the desired product (120 mg). MS (M+1)⁺: 494.5.

Step 1-5, preparation of6-(3-benzyloxy-phenyl)-3-(3-chloro-5-methyl-phenyl)-quinoline-4-carboxylicacid: to the THF solution (3 mL) of the oil from Step 1-4 (120 mg,) wasadded NaOH solution (4M, 2 mL). The resulting mixture was stirred at 75°C. for 5 h. The reaction solution was acidified with HCl solution (4.0M) to pH 2. The crude was extracted with ethyl acetate and washed withbrine, dried with MgSO₄ and concentrated to afford a brown solid. Thismaterial was used for next Step without further purification. MS (M+1)⁺:480.1.

Step 1-6, preparation of(2S)-2-({[6-(3-benzyloxy-phenyl)-3-(3-chloro-5-methyl-phenyl)-quinoline-4-carbonyl]-methyl-amino}-methyl)-pyrrolidine-1-carboxylicacid tert-butyl ester: to the DMF (0.75 mL) solution of the acid fromStep 1-5 (25 mg, 0.05 mmol) was added triethylamine (0.026 mL, 0.15mmol) and HATU (38 mg, 0.1 mmol), then2-(S)-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester(20 mg, 0.1 mmol) was added. The reaction mixture was stirred at rt for10 min. The reaction solution was diluted with EtOAc, washed with NaOH(1N, 2 mL) and brine, dried with MgSO₄, concentrated and purified bysilica gel chromatography to afford the desired product as brown oil (20mg). MS (M+1)⁺: 676.6.

Step 1-7, preparation of3-(3-chloro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide:to the oil from Step 1-6, was added trifluoroacetic acid (1 mL) andthioanisole (0.1 ml). The resulting mixture was stirred at 60° C. for 1h. Then it was concentrated and purified by a reversed-phase columnchromatography eluted with water and acetonitrile which contains 0.1% ofTFA. All factions containing desired product were combined, neutralizedwith saturated NaHCO₃ solution, then extracted with EtOAc. The organiclayer was separated, dried with MgSO₄ and concentrated. The resultingresidue was dissolved in MeOH (1 mL) and treated with HCl in EtOAc (1M,1 mL). The solution was concentrated under high vacuum to give the finalproduct (10 mg) as a HCl salt (Compound 1-1). MS (M+1)⁺: 486.3.

The following compounds were prepared similarly to Example 1 withappropriate substituting reagents and substrates at different steps:

Compound MS no. (M + H)⁺ 1-2 460.4 1-3 474.2 1-4 470.5 1-6 486.3 1-7456.5 1-18 456.5 1-73 509.6

N-[(2S)-2-aminobutyl]-6-(3-carbamoyl-5-hydroxyphenyl)-3-(3-chloro-5-methylphenyl)-N-methylquinoline-4-carboxamide(Compound 1-8) was prepared similarly except carboxamide was obtainedfrom the corresponding cyano group during saponification in Step 1-5. MS(M+1)⁺: 518.3.

Example 2:N-[(2S)-2-aminobutyl]-6-(3-cyano-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide

Step 2-1, preparation of6-chloro-3-(3-fluoro-5-methyl-phenyl)-quinoline-4-carboxylic acid methylester: to 6-chloro-3-trifluoromethanesulfonyloxy-quinoline-4-carboxylicacid methyl ester (1.85 g, 5.0 mmol), 3-fluoro-5-methylphenylboronicacid (1.16 g, 7.5 mmol), K₃PO₄.H₂O (2.3 g, 10 mmol), Pd₂dba₃/t-Bu₃P(1/1.2, 276 mg, 0.21 mmol) in THF/water (20 ml/2 ml) for 5 min. Themixture was sealed and stirred for 2 hrs. The crude was extracted withethyl acetate, then washed with brine, and concentrated. The resultedoil was purified by silica gel column chromatography eluted withhexane/ethyl acetate to yield the desired compound (1.45 g). MS (M+H)⁺:330.3.

Step 2-2, preparation of6-chloro-3-(3-fluoro-5-methyl-phenyl)-quinoline-4-carboxylic acid:6-chloro-3-(3-fluoro-5-methyl-phenyl)-quinoline-4-carboxylic acid methylester (1.45 g) obtained from the previous step was refluxed withconc.HCl (45 ml) in toluene (15 ml) for 17 hrs. LCMS showed about 50%conversion of ester to acid. Therefore, additional toluene (10 ml) andconc. HCl (10 ml) were added. The mixture was refluxed for another 10hr, cooled to rt. Toluene was removed and the gummy material in waterwas titrated with acetone to form a precipate which was filtered toyield the desired compound (1.05 g). MS (M+H)⁺: 316.2.

Step 2-3, preparation benzylN-[(2S)-1-{1-[6-chloro-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]-N-methylformamido}butan-2-yl]carbamate:a mixture of6-chloro-3-(3-fluoro-5-methyl-phenyl)-quinoline-4-carboxylic acidobtained from the previous step (0.63 g, 2 mmol), TEA (1.2 ml, 3.5 eq),HATU (1.14 g, 1.5 eq), (S)-(1-methylaminomethyl-propyl)-carbamic acidbenzyl ester (1.2 ml) were stirred in dry DMF (8 ml) for 2 hrs. Themixture was diluted with ethyl acetate, then washed with NaOH solution(0.1 N, 10 ml), water, brine and concentrated. The crude was purified bysilica gel column chromatography to give the desired product (0.95 g) asa brown oil. MS (M+H)⁺:534.4.

Step 2-4, preparation of benzylN-[(2S)-1-{1-[6-(3-cyano-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]-N-methylformamido}butan-2-yl]carbamate:to benzylN-[(2S)-1-{1-[6-chloro-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]-N-methylformamido}butan-2-yl]carbamate(267 mg, 0.5 mmol),3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile(259 mg, 1.0 mmol), Pd (amphos)Cl₂ (25 mg, 0.035 mmol), K₂:CO₃ (138 mg,1.0 mmol) in dioxane/water (4 mmol 0.4 ml), N₂ was bubbled through for 1min. The mixture was sealed and heated at 90° C. for 2 hrs. The mixturewas extracted with ethyl acetate, washed with water, brine,concentrated. The crude was purified by silica gel column chromatographyeluted with hexane/ethyl acetate to give the desired compound (300 mg).(M+H)⁺: 631.8.

Step 2-5, preparation ofN-[(2S)-2-aminobutyl]-6-(3-cyano-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide:benzylN-[(2S)-1-{1-[6-(3-cyano-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]-N-methylformamido}butan-2-yl]carbamate(300 mg, 0.48) was stirred in TFA (4 ml) in the presence of thioanisole(0.3 ml) for 1 h at 65° C. It was then concentrated and the crude waspurified by RP C18 column chromatography eluted with water/acetonitrile(both containing 0.5% of TFA) to yield the desired compound as TFA salt.The free amine was obtained by dissolving the TFA salt of the product inethyl acetate, then washed with sat NaHCO₃ solution, dried over MgSO₄,and filtered, followed by concentration. It was further converted to HClsalt by redissolving it in 6 N HCl in 2-propanol and then concentratedto remove all solvents (175 mg, Compound 1-9). (M+H)⁺: 497.5.Alternatively, HCl in isopropanol or dioxane was also used for this stepwhen Boc protecting group was used.

The following compounds were prepared similarly to Example 2 withappropriate substituting reagents and substrates at different steps:

Compound MS no. (M + H)⁺ 1-10 488.3 1-11 472.4 1-12 481.3 1-13 474.21-14 475.2 1-15 485.5 3-8 480.4 1-16 479.3 3-10 458.4 1-17 490.4 1-19483.3 1-20 471.3 1-21 509.6 1-22 501.3 1-23 492.2 1-24 497.4 1-25 501.01-26 519.2 1-27 513.4 1-28 501.3 1-29 486.4 1-30 513.4 1-31 508.4 1-32501.0 1-34 499.3 1-35 527.3 1-38 487.4 1-45 523.5 1-51 497.5 1-52 497.51-55 489.4 3-40 510.6 3-48 455.4 3-59 473.4 3-60 493.4 3-61 493.3

6-(5-carbamoylpyridin-3-yl)-3-[3-fluoro-5-(2-hydroxyethyl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide(Compound 3-58) was obtained as a side product from synthesis ofCompound 3-40 during the deprotection step (Step 2-5). (M+H)⁺: 528.1.

Example 3:3-(3-chloro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2R)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide

Step 3-1, preparation of tert-butyl(2R)-2-[({6-[3-(benzyloxy)phenyl]-3-(3-chloro-5-methylphenyl)quinolin-4-yl}formamido)methyl]pyrrolidine-1-carboxylate:to the DMF (0.75 mL) solution of the acid from Step 1-5 of Example 1 (48mg, 0.1 mmol) was added triethylamine (0.052 mL, 0.3 mmol) and HATU (76mg, 0.2 mmol), then 2-(R)-aminomethyl-pyrrolidine-1-carboxylic acidtert-butyl ester (20 mg, 0.1 mmol) was added. The reaction mixture wasstirred at rt for 1 h. The reaction solution was diluted with EtOAc,washed with NaOH (1N, 2 mL) and brine, dried with MgSO₄, concentratedand purified by silica gel chromatography to afford the desired productas brown oil (32 mg). MS (M+1)⁺: 662.5.

Step 3-2, preparation of tert-butyl(2R)-2-[(1-{6-[3-(benzyloxy)phenyl]-3-(3-chloro-5-methylphenyl)quinolin-4-yl}-N-methylformamido)methyl]pyrrolidine-1-carboxylate:to the THF (anhydrous, 2 ml) of the above oil (32 mg, 0.05 mmol), NaH(10 mg, 60% in mineral oil, 0.25 mmol) was added, followed by additionof MeI (0.02 ml, 0.3 mmol). The mixture was stirred at rt for 1 h, thenextracted with ethyl acetate. The organic layer was washed with water,brine, dried over MgSO₄, and concentrated to give an oil which was usedfor next step without further purification. MS (M+1)⁺: 676.5

Step 3-3, preparation of3-(3-chloro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2R)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide:to the oil from Step 3-2, was added trifluoroacetic acid (1 mL) andthioanisole (0.1 ml). The resulting mixture was stirred at 60° C. for 2h. Then it was concentrated and purified by a reversed-phase columnchromatography eluted with water and acetonitrile which contains 0.1% ofTFA. All factions containing desired product were combined, neutralizedwith saturated NaHCO₃ solution, then extracted with EtOAc. The organiclayer was separated, dried with MgSO₄ and concentrated. The resultingresidue was dissolved in MeOH (1 mL) and treated with HCl in EtOAc (1M,0.1 mL). The solution was concentrated to give the final product (12 mg)as a HCl salt (Compound 1-5). MS (M+1)⁺: 486.3.

Example 4:3-(3-chloro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide

Step 4-1, preparation of(2S)-2-{[1-(3-chloro-6-hydroxy-1,5-naphthyridin-4-yl)-N-methylformamido]methyl}pyrrolidine-1-carboxylate:A mixture of 3-chloro-6-hydroxy-[1,5]naphthyridine-4-carboxylic acid(449.2 mg, 2.0 mmol), (S)-2-methylaminomethyl-pyrrolidine-1-carboxylicacid benzyl ester (0.65 g, 3.0 mmol), HATU (1.14 g, 3.0 mmol), TEA (0.70ml, 4.0 mmol) was stirred in DMF (10 ml) at rt for 2 hrs. The mixturewas extracted with ethyl acetate. The organic layer was washed withwater, dried, concentrated and purified by column chromatography usingDCM and ethyl acetate as elutes to obtain the desired product (0.8 g)which is about 50% pure. MS (M+1)⁺: 455.3.

Step 4-2, preparation of benzyl(2S)-2-({1-[3-chloro-6-(trifluoromethanesulfonyloxy)-1,5-naphthyridin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate:the material from the above step (0.8 g, 0.85 mmol, 50% pure) wasdissolved in anhydrous DCM (6 ml), cooled with ice bath, then TEA (1.4ml, 8.0 mmol) was added; followed by addition oftrifluoromethanesulfonic anhydride slowly (0.7 ml, 1.5 mmol). Themixture was stirred for additional 0.5 hr and extracted with DCM.Organic layer was washed with water, concentrated and purified by silicagel column chromatography eluted with DCM/ethyl acetate to yield thedesired product (0.33 g, 50% pure). MS (M+1)⁺: 587.3.

Step 4-3, preparation of benzyl(2S)-2-[(1-{6-[3-(benzyloxy)phenyl]-3-chloro-1,5-naphthyridin-4-yl}-N-methylformamido)methyl]pyrrolidine-1-carboxylate:To the material from the above step in THF (6 ml)/water (0.5 ml),nitrogen gas was bubbled through for 10 min, followed by addition of3-benzoxylphenyl boronic acid (228 mg, 1 mmol), Pd₂dba₃.t-Bu₃P complex(40 mg, 0.03 mmol), K₃PO₄.H₂O (530.4, 2.0 mmol). The mixture was sealedand stirred at rt for 2 hrs and then extracted with ethyl acetate.Organic layer was then washed with water, dried, concentrated andpurified by silica gel column chromatography eluted with hexane/ethylacetate to yield the desired product (220 mg). MS (M+1)⁺: 621.2.

Step 4-4, preparation of benzyl(2S)-2-[(1-{6-[3-(benzyloxy)phenyl]-3-(3-chloro-5-methylphenyl)-1,5-naphthyridin-4-yl}-N-methylformamido)methyl]pyrrolidine-1-carboxylate:to the material from Step 4-3 (110 mg) in dioxane (2 ml),3-chloro-5-methylphenylboronic acid (105 mg, 0.62 mmol), K₂CO₃ (82 mg,0.6 mmol) were added. The mixture was bubbled with nitrogen for 5 min,then Pd (amphos)Cl₂ (11 mg, 0.016 mmol) was added. It was sealed andheated at 90° C. for 90 min and then directly purified by silica gelcolumn chromatography eluted with hexane/ethyl acetate to give thedesired product as a brown solid (66 mg). MS (M+1)⁺: 711.6.

Step 4-5, preparation of3-(3-chloro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide:the material obtained from the above step was heated at 65° C. with TFA(2 ml) in the presence of thioanisole (0.1 ml) for 1.5 hrs. The crudewas concentrated and purified by C18 reversed phase columnchromatography eluted with water and acetonitrile which contain 0.1%TFA. The fractions containing desired product were combined, neutralizedby NaHCO₃ solution, and extracted with ethyl acetate. The organic layerwas then dried, filtered and treated with HCl (4N, in dioxane, 0.3 ml),then concentrated to yield the desired product (22 mg) as HCl salt(Compound 2-1). MS (M+1)⁺: 487.4.

The following compounds were prepared similarly to Example 4 withappropriate substituting reagents and substrates at different steps:

Compound MS no. (M + H)⁺ 2-2 455.3 2-3 505.3 2-4 512.5 2-5 480.4 2-6500.3 2-7 484.6 2-8 505.3 2-9 475.2 2-10 510.5 2-11 466.5 2-12 496.32-13 484.5 2-14 537.5 2-15 491.3 2-16 502.4 2-17 498.2 2-18 514.5 2-19484.5 2-20 497.5 2-21 511.6 2-23 511.6 2-24 525.5 3-5 454.1 3-9 456.2

Example 5:3-(3-fluoro-5-methylphenyl)-N-methyl-6-(pyrrolidin-1-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide

Step 5-1, preparation of benzyl(2S)-2-({1-[3-chloro-6-(pyrrolidin-1-yl)-1,5-naphthyridin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate:benzyl(2S)-2-({1-[3-chloro-6-(trifluoromethanesulfonyloxy)-1,5-naphthyridin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate:(40 mg, 0.07 mmol), an intermediate from Example 4, was heated at 90° C.with pyrrolidine (17 μl, 0.1 mmol) in acetonitrile (1 ml) in thepresence of DIPEA (0.2 ml) for 1 hr, and concentrated to be used fornext step without further purification. MS (M+1)⁺:508.5.

Step 5-2, preparation of benzyl(2S)-2-({1-[3-(3-fluoro-5-methylphenyl)-6-(pyrrolidin-1-yl)-1,5-naphthyridin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate:A mixture of the material obtained from the above step,3-fluoro-5-methylphenylboronic acid (30 mg), Pd (amphos)Cl₂ (5 mg),K₂CO₃ (30 mg) was bubbled with N₂ for 10 min and then heated at 90° C.in dioxane (1 ml) under sealed condition for 2 hrs, then extracted withethyl acetate. The organic layer was separated, concentrated and usedfor next step without further purification. MS (M+1)⁺: 582.5.

Step 5-3, preparation of3-(3-fluoro-5-methylphenyl)-N-methyl-6-(pyrrolidin-1-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide:the above crude material was heated with TFA (2 ml) in the presence ofthioanisole (0.1 ml) at 65° C. for 1 h. The insoluble was filtered off,and resulted solution was concentrated and purified by a reversed phaseC18 column chromatography to yield the desired product (18 mg) as TFAsalt (Compound 3-2). MS (M+1)⁺: 448.2.

(3-(3-fluoro-5-methylphenyl)-6-(3-hydroxypiperidin-1-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide(Compound 3-3) was similarly prepared according to the method in Example5 with appropriating reagents. MS (M+1)⁺: 478.3.

Example 6:6-(3-hydroxyphenyl)-N-methyl-3-(pyrrolidin-1-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide

Step 6-1, preparation of benzyl(2S)-2-[(1-{6-[3-(benzyloxy)phenyl]-3-(pyrrolidin-1-yl)-1,5-naphthyridin-4-yl}-N-methylformamido)methyl]pyrrolidine-1-carboxylate:to benzyl(2S)-2-[(1-{6-[3-(benzyloxy)phenyl]-3-chloro-1,5-naphthyridin-4-yl}-N-methylformamido)methyl]pyrrolidine-1-carboxylate(30 mg), the intermediate from Example 4, in toluene (1 ml), Argon wasused in for 10 min, then, pyrrolidine (20 μl), Pd (OAc)₂ (2.2 mg), BINAP(6 mg) and Cs₂CO₃ (34 mg, 0.1 mmol) were added. The mixture was sealedand heated at 95° C. for 1 h, then extracted with ethyl acetate. Theorganic layer was washed with water, dried, concentrated and purified bysilica gel column chromatography to yield the desired product (4.5 mg).MS (M+1)⁺: 656.9.

Step 6-2, preparation6-(3-hydroxyphenyl)-N-methyl-3-(pyrrolidin-1-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide:the above material from Step 6-1 was heated with TFA (1 ml) in thepresence of thioanisole (0.05 ml) for 1 h, then concentrated andpurified by a reversed phase C18 column chromatography to yield thedesired product (1.8 mg, Compound 3-4). MS (M+1)⁺: 432.4.

The following compounds were prepared similarly to Example 6 withappropriate substituting reagents and substrates at different steps:

Compound MS no. (M + H)⁺ 3-6 476.3 3-11 446.4 3-12 448.2 3-17 462.3 3-20475.4 3-21 475.2 3-36 503.3 3-42 551.5 3-45 502.4 3-47 551.3 3-49 531.43-54 575.5 3-55 575.4 3-64 520.4 3-69 471.3 3-70 501.3 3-76 495.5

Example 7:6-(2-amino-5-cyanopyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide

Step 7-1, preparation of benzyl(2S)-2-({1-[6-chloro-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate:a mixture of6-chloro-3-(3-fluoro-5-methyl-phenyl)-quinoline-4-carboxylic acid,prepared in Example 2 (1.26 g, 4.0 mmol),2-(S)-methylaminomethyl-pyrrolidine-1-carboxylic acid benzyl ester (1.2g, 1.2 eq. 4.8 mmol), HATU (2.28 g, 1.5 eq), DIPEA (2 ml, 3.0 eq) wasstirred in dry DMF (10 ml) for 2 hrs. It was then diluted with ethylacetate. The organic layer was washed with water, brine and thenconcentrated. The crude was purified by silica gel column chromatographyeluted with hexane/ethyl acetate to afford the desired product (1.17 g).MS (M+1)⁺: 546.4.

Step 7-2, preparation of benzyl(2S)-2-({1-[3-(3-fluoro-5-methylphenyl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate:to the material obtained from the above step (0.59 g, 1.1 mmol), bis(pinacol)diboron (0.544 g, 2.0 mmol), Pd₂dba₃ (50 mg, 0.05 mmol), x-Phos(50 mg, 0.1 mmol), potassium acetate (300 mg, 3 mmol) in dioxane (10ml), N₂ gas was bubbled for 10 min. The mixture was then sealed andheated with stirring at 105° C. for 1 h. After it was cooled to rt, themixture was extracted with ethyl acetate, the solid was filtered off.The organics were then washed with sat. NaHCO₃, sat NH₄Cl, brine, driedand concentrated. The crude was purified by silica gel columnchromatography eluted with hexane/ethyl acetate to yield the desiredproduct as an oil (0.57 g). MS (M+1)⁺: 638.5.

Step 7-3, preparation of benzyl(2S)-2-({1-[6-(2-amino-5-cyanopyridin-3-yl)-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate:to a mixture of the material from Step 7-2 (40 mg, 0.06 mmol),6-amino-5-bromo-nicotinonitrile (14 mg, 0.07 mmol), Pd (amphos)Cl₂ (9mg, 0.2 eq), K₂CO₃ (22 mg, 2.5 eq) in dioxane/water (1 ml/0.1 mil), N₂was bubbled for 2 min, then sealed and heated at 100° C. for 1 h. Themixture was diluted with ethyl acetate and water. The organic layer wasseparated and concentrated, purified by silica gel chromatography elutedwith hexane/ethyl acetate to yield the desired product (13.6 mg). MS(M+1)⁺: 629.5.

Step 7-4, preparation of6-(2-amino-5-cyanopyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide:the material from Step 7-3 was stirred in TFA (1 ml) in the presence ofthioanisole (0.2 ml) for 1 h at 50° C. The mixture was then concentratedand purified by reversed phase C18 column chromatography to afford thedesired product (9.5 mg, Compound 3-15). MS (M+1)⁺: 495.5.

6-(5-cyano-2-hydroxypyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide(Compound 3-56) was prepared similarly according to Example 7, except atStep 7-4, hydroxyl group on side chain 5-cyano-2-hydroxy-pyridin-3-ylwas produced from the corresponding 5-cyano-2-methoxyl-pyridin-3-ylgroup by treatment of TFA. MS (M+1)⁺: 496.4.

The following compounds were prepared similarly to Example 7 withappropriate substituting reagents:

Compound MS no. (M + H)⁺ 3-13 480.4 3-14 480.3 3-16 480.4 3-19 481.31-40 547.3 1-41 504.2 1-43 514.4 3-22 508.3 1-49 526.3 3-33 526.4 3-35498.3 3-37 509.4 3-38 523.3 1-53 515.4 1-54 515.5 3-39 494.6 1-60 533.23-41 511.6 3-44 499.3 3-46 512.5 3-50 533.2 3-51 470.4 1-66 551.3 3-52533.2 1-70 528.1 3-57 512.5 3-62 488.5 3-65 469.5 3-66 509.6 3-71 456.33-67 486.4 3-72 565.5 3-73 578.3 3-74 473.3 3-75 489.3 3-77 502.4 3-78515.6 1-76 536.4 1-77 495.5 3-79 516.4 3-80 498.3 3-81 485.4 3-82 543.03-83 469.6 3-84 485.4 3-85 504.3 3-86 521.3

Example 8:6-(3-hydroxyphenyl)-N-methyl-3-(prop-1-yn-1-yl)-N-((2S)-pyrrolidin-2-ylmethyl)-1,5-naphthyridine-4-carboxamide

Step 8-1, preparation of benzyl(2S)-2-[(1-{6-[3-(benzyloxy)phenyl]-3-(prop-1-yn-1-yl)-1,5-naphthyridin-4-yl}-N-methylformamido)methyl]pyrrolidine-1-carboxylate:to benzyl(2S)-2-[(1-{6-[3-(benzyloxy)phenyl]-3-chloro-1,5-naphthyridin-4-yl}-N-methylformamido)methyl]pyrrolidine-1-carboxylate(240 mg, 0.39 mmol) from Example 4 in toluene (4 ml), tributyl(1-propynl)tin (0.37 ml, 3.0 eq) was added. The mixture was bubbled withN₂ gas for 10 min, then Pd (amphos)Cl₂ (55 mg, 0.2 eq) was added and themixture was sealed and heated at 90° C. for 2 h. Additional palladiumcatalyst (0.1 eq) and tin reagent (1.0 eq) were added. The mixture wasstirred for another 2 hrs. The crude was diluted with ethyl acetate. Theorganic solution was washed with water, dried, concentrated and purifiedby silica gel chromatography eluted with ethyl acetate/hexanes to yieldthe desired product (131 mg). MS (M+1)⁺: 625.6.

Step 8-2, preparation of6-(3-hydroxyphenyl)-N-methyl-3-(prop-1-yn-1-yl)-N-((2S)-pyrrolidin-2-ylmethyl)-1,5-naphthyridine-4-carboxamide:the above material from Step 8-1 was stirred in TFA (2 ml) in thepresence of thioanisole (0.2 ml) at 70° C. for 2 hrs, concentrated andpurified by reversed phase C18 column. The desired fractions werecollected and neutralized with aq NaHCO₃ solution. The product wasextracted with ethyl acetate. HCl in ethyl ether (1 ml, 0.5 M) wasadded. Concentration gave the desired product as HCl salt (30 mg,Compound 3-18) as a yellow foam. MS (M+1)⁺: 401.3.

6-(3-cyano-5-fluorophenyl)-N-methyl-3-(prop-1-yn-1-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide(Compound 3-7) was prepared similarly according to Example 8. MS (M+1)⁺:428.2.

Example 9:6-(3-carbamoyl-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide

6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide(Compound 1-24, 20 mg, 0.04 mmol), was stirred with NaOH (4M, 1 ml) in amixture of THF (0.5 ml) and MeOH (0.5 ml) at 70° C. for 1 h. The crudewas extracted directly with a mixed solvents of MeOH/DCM (1/4). Theextracted solution was concentrated and purified by reversed phase C18column eluted with water/TFA (99.5%/0.5%) and acetonitrile/TFA(99.5%/0.5%) to afford the desired product (6 mg, TFA salt) as whitepowder (Compound 1-33). MS (M+H)⁺:515.2.

Similarly,N-[(2S)-2-aminopropyl]-6-(3-carbamoyl-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide(Compound 1-75) was obtained fromN-[(2S)-2-aminopropyl]-6-(3-cyano-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide(Compound 1-19). MS (M+H)⁺:501.3.

Similarly,6-(3-carbamoyl-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide(Compound 2-24) was obtained from6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide(Compound 2-17). MS (M+H)⁺:516.4.

Example 10:3-fluoro-5-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]benzoicacid

6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide(Example 1-24, 70 mg, 0.14 mmol, was stirred with NaOH (4M, 2 ml) in amixture of THF (1 ml) and MeOH (1 ml) at 60-70° C. for 6 hrs. The crudewas acidified to pH ˜3, then extracted with DCM. The extracted solutionwas concentrated and purified by reversed phase C18 column eluted withwater/TFA (99.5%/0.5%) and acetonitrile/TFA (99.5%/0.5%) to afford thedesired product (25 mg, TFA salt) as white powder (Compound 1-36). MS(M+H)⁺:516.4.

Example 11:3-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]benzoicacid

Step 11-1, preparation of benzyl(2S)-2-({1-[3-(3-fluoro-5-methylphenyl)-6-[3-(methoxycarbonyl)phenyl]quinolin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate:to a mixture of benzyl(2S)-2-({1-[3-(3-fluoro-5-methylphenyl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate:(30 mg, 0.046 mmol), 3-bromo-benzoic acid methyl ester (11.2 mg, 0.05mmol), Pd (amphos)Cl₂ (6.6 mg, 0.2 eq), K₂CO₃ (16 mg, 2.5 eq) indioxane/water (1 ml/0.1 ml), N₂ was bubbled for 2 min, then sealed andheated at 100° C. for 1 h. The mixture was diluted with ethyl acetateand water. The organic layer was separated and concentrated, purified bysilica gel chromatography eluted with hexane/ethyl acetate to yield thedesired product as a white foam (11 mg). MS (M+H)⁺:512.5.

Step 11-2, preparation of3-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]benzoicacid: the above material was stirred in TFA (1 ml) in the presence ofthioanisole (0.2 ml) at 50° C. for 1 h, then concentrated and stirred ina mixture of 4N NaOH (1 ml) in the presence of THF (1 ml) and MeOH (1ml) at 60° C. for 1 h. The mixture was acidified and extracted out witha mixture of DCM/MeOH (4/1). The extract was concentrated and purifiedby reversed phase C18 column eluted with water/TFA (99.5%/0.5%) andacetonitrile/TFA (99.5%/0.5%) to afford the desired product (2.5 mg, TFAsalt, Compound 1-44). MS (M+H)⁺:498.3.

The following compounds were prepared similarly to Example 11 withappropriate substituting reagents:

Compound MS no. (M + H)⁺ 1-46 498.4 1-47 498.4 1-48 512.4 1-50 526.4

Example 12:6-(3-cyano-5-fluorophenyl)-3-[3-fluoro-5-(2-hydroxyethoxy)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide

Step 12-1, preparation of benzyl(2S)-2-({1-[6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-hydroxyphenyl)quinolin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate:title compound is obtained according to the method in Example 2 withappropriate substituting reagents. MS (M+H)⁺: 633.3.

Step 12-2, preparation of benzyl(2S)-2-({1-[6-(3-cyano-5-fluorophenyl)-3-[3-fluoro-5-(2-methoxyethoxy)phenyl]quinolin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate:a mixture of the material prepared from Step 12-1 (32 mg, 0.05 mmol) inDMF (1 ml) was stirred with K₂CO₃ (34.5 mg, 0.25 mmol) and1-bromo-2-methoxyethane (0.05 ml, 0.5 mmol) at 80° C. for 2 h. The crudewas extracted with ethyl acetate. The extract was washed with water,dried and concentrated, purified by silica gel column chromatography togive the desired product (30 mg). MS (M+H)⁺: 691.3.

Step 12-3, preparation of6-(3-cyano-5-fluorophenyl)-3-[3-fluoro-5-(2-hydroxyethoxy)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide:the above material from Step 12-2 was stirred at 65° C. in TFA (1 ml) inthe presence of thioanisole (0.1 ml) for 1 h. The mixture wasconcentrated and purified by reverse phase C18 column chromatographyeluted with water/TFA (99.5%/0.5%) and acetonitrile/TFA (99.5%/0.5%) toafford the desired product (15 mg, Compound 1-42). MS (M+H)⁺: 557.3.

6-(3-cyano-5-fluorophenyl)-3-[3-fluoro-5-(2-hydroxyethoxy)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide(Compound 1-39) was prepared similarly according to the method inExample 12 with appropriating reagents. MS (M+1)⁺: 543.2.

4-{3-[6-(3-cyano-5-fluorophenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-3-yl]-5-fluorophenoxy}butanoicacid (Compound 1-37) was prepared similarly according to the method inExample 12 with appropriating reagents and with an additional hydrolysisstep of the ester. MS (M+1)⁺: 585.3.

2-{3-fluoro-5-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]phenyl}aceticacid (Compound 1-59) was prepared similarly according to the method inExample 12 with appropriating reagents and with an additional hydrolysisstep of the ester. MS (M+1)⁺:530.2.

2-{3-chloro-5-[6-(3-cyano-5-fluorophenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-3-yl]phenoxy}aceticacid (Compound 1-65) was prepared similarly according to the method inExample 12 with appropriating reagents and with an additional hydrolysisstep of the ester. MS (M+1)⁺: 573.3.

Example 13:6-(3-cyano-5-fluorophenyl)-3-(2-fluoro-3,5-dimethylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide

Step 13-1, preparation of6-chloro-3-methoxymethoxy-quinoline-4-carboxylic acid: a mixture of6-chloro-3-methoxymethoxy-quinoline-4-carboxylic acid methyl ester (2.0g, 7.1 mmol) in THF/MeOH (5 ml/5 ml) was stirred with 4 N NaOH (10 ml)at 70° C. until TLC showed no starting material left. The mixture wasacidified and extracted with ethyl acetate, dried and concentrated togive a white solid (0.8 g). MS (M+1)⁺: 268.3.

Step 13-2, preparation of benzyl(2S)-2-({1-[6-chloro-3-(methoxymethoxy)quinolin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate:a mixture of the acid obtained from Step 13-1, HATU (1.71 g, 4.5 mmol),(S)-2-methylaminomethyl-pyrrolidine-1-carboxylic acid benzyl ester (0.9g, 3.6 mmol), TEA (1.0 ml, 6 mmol) were stirred in DMF (15 ml) for 1 h.The mixture was diluted with water and extracted with ethyl acetate.Ethyl acetate layer was then dried, concentrated and purified by silicagel chromatography eluted with DCM/ethyl acetate to give the desiredproduct (1.4 g) as a brown oil. MS (M+1)⁺: 498.3.

Step 13-3, preparation of benzyl(2S)-2-({1-[6-(3-cyano-5-fluorophenyl)-3-(ethoxymethoxy)quinolin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate:To the material from Step 13-2 (0.7 g, 1.4 mmol) in a mixture of dioxane(7 ml) and water (0.7 ml), 3-cyano-5-fluoro-phenyl boronic acid (462 mg,2.8 mmol), K₂CO₃ (386 mg, 2.8 mmol) were added. The solution was bubbledwith N₂ for 10 min, then Pd (amphos)Cl₂ (35 mg, 0.05 mmol) was added.The mixture was sealed and heated with stirring at 95° C. for 2 hrs.Additional boronic acid (1 mmol) and Pd (amphos)Cl₂ (15 mg), K₂CO₃ (1mmol) were added. It was heated for another 1 hr, extracted with ethylacetate. The ethyl acetate was concentrated and the crude was purifiedby silica column chromatography eluted with DCM/ethyl acetate to givethe desired product (640 mg). MS (M+1)⁺: 583.2.

Step 13-4, preparation of benzyl(2S)-2-({1-[6-(3-cyano-5-fluorophenyl)-3-(trifluoromethanesulfonyloxy)quinolin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate:the above material from Step 13-3 was stirred in isopropanol containing7N HCl (7 ml) for 3 hrs, and concentrated to yield a yellow solid. Thesolid was then dissolved in DCM (7 ml), cooled to 0° C., followed byaddition of TEA (0.8 ml, 4.4 mmol) and trifluoromethanesulfonicanhydride (0.4 mmol, 2.2 mmol). The mixture was stirred at rt for 1 hrand diluted with water and extracted with ethyl acetate. The ethylacetate was concentrated and the crude was purified by silica gel columnchromatography eluted with hexane/ethyl acetate to yield the desiredproduct (517 mg). MS (M+1)⁺: 671.5.

Step 13-5, preparation of benzyl(2S)-2-({1-[6-(3-cyano-5-fluorophenyl)-3-(2-fluoro-3,5-dimethylphenyl)quinolin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate:the desired product (30 mg) was obtained by following the methodoutlined in Step 13-3 with the material made in Step 13-4 (55 mg) and3,5-dimethyl-2-fluorophenylboronic acid, pinacol ester (50 mg). MS(M+1)⁺: 645.7.

Step 13-5, preparation of6-(3-cyano-5-fluorophenyl)-3-(2-fluoro-3,5-dimethylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide:the material from the above step was heated in TFA (1.5 ml) in thepresence of thioanisole (0.15 ml) for 1 hr, concentrated and purified byreversed phase C18 column to give the desired product as TFA salt whichwas then diluted with ethyl acetate and washed with sat NaHCO₃ aqueoussolution (1 ml), and then treated with 4 N HCl in dioxane (0.1 ml) toform HCl salt (15 mg, Compound 3-34). MS (M+1)⁺: 511.4.

The following compounds were prepared similarly to Example 13 withappropriate substituting reagents:

Compound MS no. (M + H)⁺ 1-56 501.1 1-57 513.4 1-58 497.4 1-67 501.31-69 541.3

6-(3-cyano-5-fluorophenyl)-3-[3-fluoro-5-(prop-1-en-2-yl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide(Compound 1-71) was obtained as side product during the preparation of6-(3-cyano-5-fluorophenyl)-3-[3-fluoro-5-(2-hydroxypropan-2-yl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide(Compound 1-69).

Example 14:6-(3,5-difluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide

Step 14-1: preparation of6-(3,5-difluoro-phenyl)-3-(3-fluoro-5-methyl-phenyl)-quinoline-4-carboxylicacid methyl ester: a mixture of6-chloro-3-(3-fluoro-5-methyl-phenyl)-quinoline-4-carboxylic acid methylester from Step 2-1 of Example 2 (0.9 g, 2.7 mmol) and the3,5-difluorophenyl boronic acid (0.86 g, 2.0 eq.), Pd (amphos)Cl₂ (250mg), and K₂CO₃ (750 mg, 2 eq.) in dioxane containing 10% of water (22ml) was degassed by N₂ for 3 min and sealed, heated at 90° C. for 2 hrs.The mixture was diluted with ethyl acetate. The ethyl acetate layer wasthen washed with 1N HCl, brine and concentrated. The crude oil waspurified by silica gel chromatography to afford the title compound (1.0g). MS (M+1)⁺: 408.3.

Step 14-2: preparation of6-(3,5-difluoro-phenyl)-3-(3-fluoro-5-methyl-phenyl)-quinoline-4-carboxylicacid: A mixture of the ester from Step 14-1 (0.9 g, 2.2 mmol) and NaOH(4 N, 5.5 ml, 10 eq.) in THF/water (10 ml/3 ml) was stirred at 60° C.overnight, then concentrated to remove volatile. The residue wasacidified with 1 N HCl to form a precipitate, which was filtered, washedwith water, dried to afford the title compound (0.7 g). MS (M+1)⁺:394.1.

Step 14-3: preparation of tert-butyl(2S)-2-({1-[6-(3,5-difluorophenyl)-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate:a mixture of the acid from Step 14-2 (30 mg, 0.076 mmol), HATU (44 mg,1.5 eq) and triethylamine (30 ml, 3.0 eq.) in DMF (1.5 ml) was stirredat r.t for 5 min, then (S)-2-methylaminomethyl-pyrrolidine-1-carboxylicacid tert-butyl ester (20 mg, 1.2 eq) was added. The mixture was stirredfor another 2 hrs, then diluted with ethyl acetate, washed with 1N HCl,dried and concentrated. The crude was purified by silica gelchromatography to afford the title compound (30 mg). MS (M+1)⁺: 590.4.

Step 14-4, preparation of6-(3,5-difluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide:the product from the above step was stirred in a mixture of DCM (1.5 ml)and TFA (0.15 ml) for 2 hr at r,t. The mixture was then concentrated andpurified by RP C18 column to yield the titled compound (10 mg, Compound1-62). MS (M+1)⁺: 490.3.

The following compounds were prepared similarly to Example 14 withappropriate substituting reagents:

Compound MS no. (M + H)⁺ 1-61 476.4 1-63 494.3 1-64 518.5 3-53 485.41-68 492.4

Example 15:6-(3-cyano-5-fluorophenyl)-N-methyl-3-(3-methylbutyl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide

To benzyl(2S)-2-({1-[3-chloro-(3-cyano-5-fluorophenyl)-1,5-naphthyridin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate(30 mg, 0.054 mmol), prepared according to the methods provided inExample 4 (Step 4-3) with 3-cyano-5-fluorophenylboronic acid assubstitution, in anhydrous THF (3 ml), Pd(t-Bu₃P)₂ (11 mg, 0.022 mmol)and 3-methylbutylzinc bromide solution (0.5M in THF, 0.32 ml, 0.16 mmol)were added. The mixture was bubbled with N₂ for 5 min and then sealedand heated at 95° C. overnight. The mixture was then diluted with water,extracted with ethyl acetate, concentrated and purified by silica gelchromatography and reversed phased C18 column chromatography to affordbenzyl(2S)-2-({1-[6-(3-cyano-5-fluorophenyl)-3-(3-methylbutyl)-1,5-naphthyridin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate(3.5 mg) as a white solid. MS (M+1)⁺: 594.4. The solid was then stirredwith TFA in the presence of thioanisole (0.25 ml/0.05 ml) at 60° C. for2 hrs and then purified by reversed phase C18 column chromatography toafford the title compound as TFA salt (1.1 mg) as off-white gum(Compound 3-43). MS (M+1)⁺: 460.3.

Example 16:6-[3-(carbamoylmethyl)-5-fluorophenyl]-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide

A mixture of2-{3-[4-({[(2S)-1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl]methyl}(methyl)carbamoyl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluorophenyl}aceticacid (21 mg, 0.027 mmol), obtained according to Step 7-3 of Example 7with (3-bromo-5-fluoro-phenyl)-acetic acid as coupling reagent, DIPEA(0.05 ml, 10 eq), HATU (31 mg, 0.041 mmol, 1.5 eq) in DMF (3 ml) wasstirred at rt for 5 min, then NH₄Cl (7.4 mg, 0.14 mmol, 5 eq) was added.The mixture was stirred overnight and another portions of HATU (76 mg),DIPEA (0.1 ml) and NH₄Cl (7.4 mg) were added. The mixture was stirredfor another 24 hrs and directly purified by reversed phase C18 columnchromatography to afford tert-butyl(2S)-2-[(1-{6-[3-(carbamoylmethyl)-5-fluorophenyl]-3-(3-fluoro-5-methylphenyl)quinolin-4-yl}-N-methylformamido)methyl]pyrrolidine-1-carboxylate(9.5 mg). MS (M+1)⁺: 663.4. The above material was treated with TFA inthe presence of thioanisole according to the previously describedprocedure to afford the title compound (2.2 mg, Compound 1-74). MS(M+1)⁺: 529.3.

Example A-1: Parenteral Pharmaceutical Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection (subcutaneous, intravenous), 1-100 mg of awater-soluble salt of a compound Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, is dissolved in sterile water andthen mixed with 10 mL of 0.9% sterile saline. A suitable buffer isoptionally added as well as optional acid or base to adjust the pH. Themixture is incorporated into a dosage unit form suitable foradministration by injection

Example A-2: Oral Solution

To prepare a pharmaceutical composition for oral delivery, a sufficientamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, is added to water (with optional solubilizer(s), optionalbuffer(s) and taste masking excipients) to provide a 20 mg/mL solution.

Example A-3: Oral Tablet

A tablet is prepared by mixing 20-50% by weight of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, 20-50% by weight ofmicrocrystalline cellulose, 1-10% by weight of low-substitutedhydroxypropyl cellulose, and 1-10% by weight of magnesium stearate orother appropriate excipients. Tablets are prepared by directcompression. The total weight of the compressed tablets is maintained at100-500 mg.

Example A-4: Oral Capsule

To prepare a pharmaceutical composition for oral delivery, 10-500 mg ofa compound of Formula (I), or a pharmaceutically acceptable saltthereof, is mixed with starch or other suitable powder blend. Themixture is incorporated into an oral dosage unit such as a hard gelatincapsule, which is suitable for oral administration.

In another embodiment, 10-500 mg of a compound of Formula (I), or apharmaceutically acceptable salt thereof, is placed into Size 4 capsule,or size 1 capsule (hypromellose or hard gelatin) and the capsule isclosed.

Example A-5: Topical Gel Composition

To prepare a pharmaceutical topical gel composition, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, is mixedwith hydroxypropyl cellulose, propylene glycol, isopropyl myristate andpurified alcohol USP. The resulting gel mixture is then incorporatedinto containers, such as tubes, which are suitable for topicaladministration.

Example B-1: SSTR Assays Membrane Preparation:

Crude membrane fractions are prepared from Chinese hamster ovary (CHO)cells stably expressing one of the five human or rodent somatostatinreceptor subtypes. The cells are grown to 85-100% confluence on standardtissue culture dishes in DM-MEM growth media (Gibco) with followingadditives: 10% fetal bovine serum (Gibco), 100 U/mL penicillin (Gibco),100 ug/mL streptomycin (Gibco), 10 mM HEPES (Gibco), 0.5 mg/mL G-418(Gibco). To prepare membranes, cells are washed once with 1× Dulbecco'sphosphate buffered saline (Gibco) containing 10 mM HEPES (Gibco) thenonce with sodium free binding buffer (50 mM Tris Base, 5 mM MgCl₂-6H₂0and 1 mM EGTA adjusted to pH 7.8). The cells are then scraped intobinding buffer containing a protease inhibitor cocktail (100 ug/mLpepstatin A (Sigma), 50 ug/mL leupeptin (Sigma), 25 ug/mL aprotinin(Sigma) and 10 mg/mL Bacitracin (USB Corporation)). The cells arecentrifuged at 43,500×g, homogenized, and the resulting membranes arecollected by centrifugation at 67,000×g. The membranes are thenresuspended in binding buffer containing the protease inhibitor cocktailusing a glass dounce homogenizer.

Functional Assay for SSTR2 Agonists

General overview: All five SSTR subtypes are Gi coupled G-proteincoupled receptors (GPCRs) that lead to decreases in intracellular cyclicAMP (cAMP) when activated by an agonist. Therefore, measurement ofintracellular cAMP levels can be used to assess whether compounds of theinvention are agonists of SSTR subtypes (John Kelly, Troy Stevens, W.Joseph Thompson, and Roland Seifert, Current Protocols in Pharmacology,2005, 2.2.1-2.2). One example of an intracellular cAMP assay isdescribed below.

cAMP Assay Protocol:

One day prior to the assay, 40,000 Chinese hamster ovary (CHO) cellsexpressing the human somatostatin receptor subtype 2 are plated in eachwell of a 96-well tissue culture plate in DM-MEM growth media (Gibco)with the following additives: 10% fetal bovine serum (Gibco), 100 U/mLpenicillin (Gibco), 100 ug/mL streptomycin (Gibco), 10 mM HEPES (Gibco),1.2 mM sodium hydroxide, 0.5 mg/mL G-418 (Gibco)). The cells arecultured overnight at 37° C., 5% CO₂ and 95% humidity. On the day of theassay, the media is aspirated and the cells are washed with 1×Dulbecco's phosphate buffered saline (Gibco). Next, 5 μL of assay buffer(lx Earle's Balanced Salt Solution (Gibco), 5 mM MgCl₂, 10 mM HEPES,0.1% bovine serum albumin, 0.2 mM 3-Isobutyl-1-methylxanthine (IBMX,Biomol Research Labs)) and forskolin is added. Various dilutions of thecompounds of the invention are prepared in assay buffer and 5 μL of thedilutions are added to the cultured cells and incubated for 15 minutesat 37° C. (the final concentration of the compounds of the invention aretypically 0-10,000 nM). 10 μL of lysis buffer (HRTF cAMP kit, Cisbio)containing cAMP detection and visualization antibodies are added and theassay is allowed incubate for 1-24 hours at room temperature. Theintracellular cAMP concentrations are then measured using a commerciallyavailable detection kit (for example, the cAMP HTRF kit, Cisbio). Themeasured intracellular cAMP concentrations are plotted vs. theconcentration of the compounds of the invention and the EC₅₀ of thecompounds are calculated using standard methods.

Illustrative biological activity of compounds is demonstrated byevaluating the inhibition of cAMP activities via sst2 receptor.Compounds having EC₅₀ between 100 nM and 1,000 nM include 1-8, 1-73,2-2, 2-4, 2-8, 2-15, 2-20, 2-21, 2-22, 3-2, 3-3, 3-5, 3-7, 3-10, 3-11,3-12, 3-17, 3-18, 3-42, 3-47, 3-49, 3-54, 3-55, 3-69, 3-70, 3-76.Compounds having EC₅₀ below 100 nM include 1-1 to 1-7, 1-9 to 1-72, 1-74to 1-78, 2-1, 2-3, 2-5, 2-6, 2-7, 2-9 to 2-14, 2-16 to 2-19, 2-23, 2-24,3-1, 3-4, 3-6, 3-8, 3-9, 3-13 to 3-16, 3-19 to 3-41, 3-43 to 3-46, 3-48,3-50 to 3-53, 3-56 to 3-68, 3-71 to 3-75, 3-77 to 3-86. A generalpreference for the S-stereochemistry at the diamino position of thecompounds of Formula (I) was observed versus the correspondingR-stereochemistry. For example, the EC₅₀ of S isomer (1-1) is 0.12 nM,while EC₅₀ of its corresponding R isomer (1-5) is 39 nM in human sst2receptor cAMP assay.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

What is claimed is:
 1. A compound that has the structure of Formula (I),or a pharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof:

wherein: R¹ and R² are taken together with the carbon atom to which theyare attached to form —C(═O)—; or R¹ and R² are each independentlyselected from the group consisting of hydrogen, and unsubstituted orsubstituted C₁-C₆alkyl; R^(A) is hydrogen, halogen, unsubstituted orsubstituted C₁-C₆alkyl, unsubstituted or substituted C₂-C₆alkenyl,unsubstituted or substituted C₂-C₆alkynyl, unsubstituted or substitutedC₁-C₆heteroalkyl, unsubstituted or substituted monocyclic carbocycle,unsubstituted or substituted bicyclic carbocycle, unsubstituted orsubstituted monocyclic heterocycle, or unsubstituted or substitutedbicyclic heterocycle, wherein if R^(A) is substituted then R^(A) issubstituted with 1-2 R¹⁰ and 0-2 R¹¹; R^(B) is unsubstituted orsubstituted C₁-C₆alkyl, unsubstituted or substituted C₂-C₆alkenyl,unsubstituted or substituted C₂-C₆alkynyl, unsubstituted or substitutedC₁-C₆heteroalkyl, unsubstituted or substituted monocyclic carbocycle,unsubstituted or substituted bicyclic carbocycle, unsubstituted orsubstituted monocyclic heterocycle, unsubstituted or substitutedbicyclic heterocycle, wherein if R^(B) is substituted then R^(B) issubstituted with 1-2 R¹² and 0-2 R¹³; A¹, A², and A³ are independentlyCR^(C) or N; each R^(C) is independently hydrogen, halogen,unsubstituted or substituted C₁-C₄alkyl, unsubstituted or substitutedC₁-C₄fluoroalkyl, unsubstituted or substituted C₁-C₄alkoxy,unsubstituted or substituted C₁-C₄fluoroalkoxy, —CN, —OH, —CO₂R¹⁴,—C(═O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —NR¹⁴C(═O)R¹⁵, —SR¹⁴, —S(═O)R¹⁵, —SO₂R¹⁵ or—SO₂NR¹⁴R¹⁵; R³ and R⁴ are independently hydrogen, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆fluoroalkyl,or unsubstituted or substituted C₃-C₆cycloalkyl, wherein any substitutedgroup of R³ and R⁴ is substituted with 1-4 R¹⁶; or R³ and R⁴ are takentogether with the nitrogen atom to which they are attached to form anunsubstituted or substituted monocyclic or bicyclic heterocyclic ring,wherein if the heterocyclic ring is substituted then the heterocyclicring is substituted with 1-4 R¹⁶; R⁵, R⁶, R⁷, and R⁸ are eachindependently selected from the group consisting of hydrogen,unsubstituted or substituted C₁-C₆ alkyl, and unsubstituted orsubstituted C₁-C₆fluoroalkyl, unsubstituted or substituted monocycliccarbocycle, unsubstituted or substituted monocyclic heterocycle, whereinany substituted group of R⁵, R⁶, R⁷, and R⁸ is substituted with 1-4 R¹⁶;R⁹ is hydrogen, unsubstituted or substituted C₁-C₆ alkyl, unsubstitutedor unsubstituted or substituted benzyl, wherein if R⁹ is substitutedthen R⁹ is substituted with 1-4 R¹⁶; or R⁴ and any one of R⁵, R⁷, or R⁹are taken together with the intervening atoms to which they are attachedto form an unsubstituted or substituted monocyclic 4- to 7-memberedheterocyclic ring or an unsubstituted or substituted bicyclic 9- to12-membered heterocyclic ring, wherein if the heterocyclic ring issubstituted then the heterocyclic ring is substituted with 1-4 R¹⁶; orR⁵ and any one of R⁶, R⁷ or R⁹ are taken together with the interveningatoms to which they are attached to form an unsubstituted or substitutedmonocyclic 4- to 7-membered ring or a bicyclic 9- to 12-membered ring,wherein if the heterocyclic ring is substituted then the heterocyclicring is substituted with 1-4 R¹⁶; or R⁷ and R⁹ are taken together withthe intervening atoms to which they are attached to form anunsubstituted or substituted monocyclic 4- to 7-membered heterocyclicring or an unsubstituted or substituted bicyclic 9- to 12-memberedheterocyclic ring, wherein if the heterocyclic ring is substituted thenthe heterocyclic ring is substituted with 1-4 R¹⁶; each R¹⁰, R¹¹, R¹²and R¹³ is independently hydrogen, halogen, unsubstituted or substitutedC₁-C₄alkyl, unsubstituted or substituted C₁-C₄alkoxy, unsubstituted orsubstituted C₁-C₄fluoroalkyl, unsubstituted or substitutedC₁-C₄fluoroalkoxy, unsubstituted or substituted monocyclic carbocycle,unsubstituted or substituted monocyclic heterocycle, —CN, —OH, —CO₂R¹⁴,—CH₂CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵, —CH₂C(═O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —CH₂NR¹⁴R¹⁵,—NR¹⁴C(═O)R¹⁵, —CH₂NR¹⁴C(═O)R¹⁵, —SR¹⁴, —S(═O)R¹⁵, —SO₂R¹⁵, or—SO₂NR¹⁴R¹⁵, wherein if any group of R¹⁰, R¹¹, R¹² and R¹³ issubstituted then the substituted group of R¹⁰, R¹¹, R¹² and R¹³ issubstituted with 1-4 R¹⁶; each R¹⁶ is independently halogen, C₁-C₆alkyl,heterocycle, —CN, —OR¹⁴, —CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵,—NR¹⁴C(═O)R¹⁵, —SR¹⁴, —S(═O)R¹⁵, —SO₂R¹⁵, or —SO₂NR¹⁴R¹⁵; each R¹⁴ isindependently selected from H, unsubstituted or substituted C₁-C₆alkyl,unsubstituted or substituted C₁-C₆heteroalkyl, substituted orunsubstituted unsubstituted or substituted C₃-C₁₀cycloalkyl, substitutedor unsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; each R¹⁵ isindependently selected from H, unsubstituted or substituted C₁-C₆alkyl,unsubstituted or substituted C₁-C₆heteroalkyl, substituted orunsubstituted unsubstituted or substituted C₃-C₁₀cycloalkyl, substitutedor unsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; or R¹⁴ and R¹⁵ aretaken together with the N atom to which they are attached to asubstituted or unsubstituted N-containing heterocycle; m is 1, 2, 3, or4.
 2. The compound of claim 1, or a pharmaceutically acceptable salt,solvate, diastereomeric mixture, individual enantiomers or prodrugthereof, wherein: R¹ and R² are taken together with the carbon atom towhich they are attached to form —C(═O)—; m is 1 or
 2. 3. The compound ofclaim 1 or claim 2, or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof,wherein: A¹, A², and A³ are CR^(C).
 4. The compound of claim 1 or claim2, or a pharmaceutically acceptable salt, solvate, diastereomericmixture, individual enantiomers or prodrug thereof, wherein: A¹ is N;and A² and A³ are CR^(C).
 5. The compound of claim 1 or claim 2, or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: A¹ and A³ areCR^(C); and A² is N.
 6. The compound of claim 1 or claim 2, or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: A¹ and A² areCR^(C); and A³ is N.
 7. The compound of claim 1 or claim 2, or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: A¹ and A² are N; andA³ is CR^(C).
 8. The compound of claim 1 or claim 2, or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: A¹ and A³ are N; andA² is CR^(C).
 9. The compound of any one of claims 1-8, or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: R³ and R⁴ are eachindependently selected from the group consisting of hydrogen,unsubstituted or substituted C₁-C₆ alkyl, and unsubstituted orsubstituted C₁-C₆fluoroalkyl, wherein any substituted group of R³ and R⁴is substituted with 1-4 R¹⁶.
 10. The compound of any one of claims 1-9,or a pharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: R³ is hydrogen; R⁶is hydrogen; and R⁸ is hydrogen.
 11. The compound of claim 1, whereinthe compound of Formula (I) has the structure of Formula (Ia), or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof:


12. The compound of claim 1, wherein the compound of Formula (I) has thestructure of Formula (Ib), or a pharmaceutically acceptable salt,solvate, diastereomeric mixture, individual enantiomers or prodrugthereof:


13. The compound of claim 1, wherein the compound of Formula (I) has thestructure of Formula (Ic), or a pharmaceutically acceptable salt,solvate, diastereomeric mixture, individual enantiomers or prodrugthereof:


14. The compound of claim 1, wherein the compound of Formula (I) has thestructure of Formula (Id), or a pharmaceutically acceptable salt,solvate, diastereomeric mixture, individual enantiomers or prodrugthereof:


15. The compound of claim 1, wherein the compound of Formula (I) has thestructure of Formula (Ie), or a pharmaceutically acceptable salt,solvate, diastereomeric mixture, individual enantiomers or prodrugthereof:


16. The compound of claim 1, wherein the compound of Formula (I) has thestructure of Formula (If), or a pharmaceutically acceptable salt,solvate, diastereomeric mixture, individual enantiomers or prodrugthereof:


17. The compound of any one of claims 1-16, or a pharmaceuticallyacceptable salt, solvate, diastereomeric mixture, individual enantiomersor prodrug thereof, wherein: each R^(C) is independently hydrogen, F,Cl, Br, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl,tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy,ethoxy, trifluormethoxy, —CN, —OH, —CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵,—C(═NOR¹⁴)R¹⁵, —SR, —S(═O)(C₁-C₄alkyl), —SO₂(C₁-C₄alkyl), or—SO₂NR¹⁴R¹⁵.
 18. The compound of any one of claims 1-17, or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: each R^(C) isindependently hydrogen, F, Cl, Br, methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, sec-butyl, tert-butyl, monofluoromethyl,difluoromethyl, trifluoromethyl, methoxy, ethoxy, trifluormethoxy, —CN,or —OH.
 19. The compound of any one of claims 1-18, or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: R^(A) is hydrogen,halogen, unsubstituted or substituted C₁-C₆alkyl, unsubstituted orsubstituted C₂-C₆alkenyl, unsubstituted or substituted C₂-C₆alkynyl, orunsubstituted or substituted C₁-C₆heteroalkyl, wherein if R^(A) issubstituted then R^(A) is substituted with 1-2 R¹⁰ and 0-2 R¹¹;
 20. Thecompound of any one of claims 1-18, or a pharmaceutically acceptablesalt, solvate, diastereomeric mixture, individual enantiomers or prodrugthereof, wherein: R^(A) is a cyclic ring that is an unsubstituted orsubstituted monocyclic carbocycle, unsubstituted or substituted bicycliccarbocycle, unsubstituted or substituted monocyclic heterocycle, orunsubstituted or substituted bicyclic heterocycle, wherein if R^(A) issubstituted then R^(A) is substituted with 1-2 R¹⁰ and 0-2 R¹¹;
 21. Thecompound of any one of claims 1-18, or a pharmaceutically acceptablesalt, solvate, diastereomeric mixture, individual enantiomers or prodrugthereof, wherein: R^(A) is an unsubstituted or substituted monocycliccarbocycle, or unsubstituted or substituted bicyclic carbocycle, whereinif R^(A) is substituted then R^(A) is substituted with 1-2 R¹⁰ and 0-2R¹¹.
 22. The compound of claim 21, or a pharmaceutically acceptablesalt, solvate, diastereomeric mixture, individual enantiomers or prodrugthereof, wherein: R^(A) is an unsubstituted or substituted monocycliccarbocycle selected from unsubstituted or substituted phenyl,unsubstituted or substituted cyclopropyl, unsubstituted or substitutedcyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted orsubstituted cyclopentenyl, unsubstituted or substituted cyclohexyl orunsubstituted or substituted cyclohexenyl, wherein if R^(A) issubstituted then R^(A) is substituted with 1-2 R¹⁰ and 0-2 R¹¹.
 23. Thecompound of any one of claims 1-18, or a pharmaceutically acceptablesalt, solvate, diastereomeric mixture, individual enantiomers or prodrugthereof, wherein: R^(A) is an unsubstituted or substituted phenyl,wherein if R^(A) is substituted then R^(A) is substituted with 1-2 R¹⁰and 0-2 R¹¹.
 24. The compound of any one of claims 1-18, or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: R^(A) is

n is 0, 1, or
 2. 25. The compound of any one of claims 1-18, or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: R^(A) is


26. The compound of any one of claims 1-18, or a pharmaceuticallyacceptable salt, solvate, diastereomeric mixture, individual enantiomersor prodrug thereof, wherein: R^(A) is an unsubstituted or substitutedbicyclic carbocycle selected from unsubstituted or substituted naphthyl,unsubstituted or substituted indanyl, unsubstituted or substitutedindenyl, or unsubstituted or substituted tetrahyodronaphthyl, wherein ifR^(A) is substituted then R^(A) is substituted with 1-2 R¹⁰ and 0-2 R¹¹.27. The compound of any one of claims 1-18, or a pharmaceuticallyacceptable salt, solvate, diastereomeric mixture, individual enantiomersor prodrug thereof, wherein: R^(A) is an unsubstituted or substitutedmonocyclic heterocycle containing 1-4 N atoms and 0 or 1 or S atom,unsubstituted or substituted monocyclic heterocycle containing 0-4 Natoms and 1 O or S atoms, unsubstituted or substituted bicyclicheterocycle containing 1-4 N atoms and 0 or 1 O or S atoms, orunsubstituted or substituted bicyclic heterocycle containing 0-4 N atomsand 1 O or S atoms, wherein if R^(A) is substituted then R^(A) issubstituted with 1-2 R¹⁰ and 0-2 R¹¹.
 28. The compound of claim 27, or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: R^(A) is anunsubstituted or substituted monocyclic heterocycle selected fromunsubstituted or substituted furanyl, unsubstituted or substitutedpyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted orsubstituted thiazolyl, unsubstituted or substituted imidazolyl,unsubstituted or substituted pyrazolyl, unsubstituted or substitutedtriazolyl, unsubstituted or substituted tetrazolyl, unsubstituted orsubstituted isoxazolyl, unsubstituted or substituted isothiazolyl,unsubstituted or substituted oxadiazolyl, unsubstituted or substitutedthiadiazolyl, unsubstituted or substituted pyridinyl, unsubstituted orsubstituted pyrimidinyl, unsubstituted or substituted pyrazinyl,unsubstituted or substituted pyridazinyl, and unsubstituted orsubstituted triazinyl, wherein if R^(A) is substituted then R^(A) issubstituted with 1-2 R¹⁰ and 0-2 R¹¹.
 29. The compound of claim 27, or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: R^(A) is anunsubstituted or substituted bicyclic heterocycle selected fromunsubstituted or substituted quinolinyl, unsubstituted or substitutedisoquinolinyl, unsubstituted or substituted quinazolinyl, unsubstitutedor substituted quinoxalinyl, unsubstituted or substitutednaphthyridinyl, unsubstituted or substituted indolyl, unsubstituted orsubstituted indazolyl, unsubstituted or substituted benzoxazolyl,unsubstituted or substituted benzisoxazolyl, unsubstituted orsubstituted benzofuranyl, unsubstituted or substituted benzothienyl,unsubstituted or substituted benzothiazolyl, unsubstituted orsubstituted benzimidazolyl, unsubstituted or substituted purinyl,unsubstituted or substituted cinnolinyl, unsubstituted or substitutedphthalazinyl, unsubstituted or substituted pteridinyl, unsubstituted orsubstituted pyridopyrimidinyl, unsubstituted or substitutedpyrazolopyrimidinyl, unsubstituted or substituted azaindolyl,unsubstituted or substituted indolinyl, unsubstituted or substitutedisoindolinyl, unsubstituted or substituted indolinonyl, unsubstituted orsubstituted isoindolinonyl, or unsubstituted or substitutedquinolinonyl, wherein if R^(A) is substituted then R^(A) is substitutedwith 1-2 R¹⁰ and 0-2 R¹¹.
 30. The compound of any one of claims 1-29, ora pharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: each R¹⁰ isindependently hydrogen, halogen, unsubstituted or substitutedC₁-C₄alkyl, unsubstituted or substituted C₁-C₄alkoxy, unsubstituted orsubstituted C₁-C₄fluoroalkyl, unsubstituted or substitutedC₁-C₄fluoroalkoxy, unsubstituted or substituted monocyclic carbocycle,unsubstituted or substituted monocyclic heterocycle, —CN, —OH, —CO₂R¹⁴,—CH₂CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵, —CH₂C(═O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —CH₂NR¹⁴R¹⁵,—NR¹⁴C(═O)R¹⁵, —CH₂NR¹⁴C(═O)R¹⁵, —SR¹⁴, —S(═O)R¹⁵, —SO₂R¹⁵, or—SO₂NR¹⁴R¹⁵, wherein if R¹⁰ is substituted then R¹⁰ is substituted with1-4 R¹⁶; each R¹¹ is independently hydrogen, halogen, unsubstituted orsubstituted C₁-C₄alkyl, unsubstituted or substituted C₁-C₄alkoxy,unsubstituted or substituted C₁-C₄fluoroalkyl, unsubstituted orsubstituted C₁-C₄fluoroalkoxy, —CN, or —OH, wherein if R¹¹ issubstituted then R¹¹ is substituted with 1-4 R¹⁶.
 31. The compound ofany one of claims 1-30, or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof,wherein: each R¹⁰ is independently hydrogen, halogen, unsubstituted orsubstituted C₁-C₄alkyl, unsubstituted or substituted C₁-C₄alkoxy,C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, unsubstituted or substitutedphenyl, unsubstituted or substituted monocyclic heterocycle, —CN, —OH,—CO₂R¹⁴, —CH₂CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵, —CH₂C(═O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵,—CH₂NR¹⁴R¹⁵, —NR¹⁴C(═O)R¹⁵, or —CH₂NR¹⁴C(═O)R¹⁵, wherein if R¹⁰ issubstituted then R¹⁰ is substituted with 1-4 R¹⁶; and each R¹¹ isindependently hydrogen, halogen, unsubstituted or substitutedC₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkoxy, or —CN,wherein if R¹¹ is substituted then R¹¹ is substituted with —OR¹⁴ or—NR¹⁴R¹⁵.
 32. The compound of any one of claims 1-31, or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: R^(B) is a cyclicring that is an unsubstituted or substituted monocyclic carbocycle,unsubstituted or substituted bicyclic carbocycle, unsubstituted orsubstituted monocyclic heterocycle, unsubstituted or substitutedbicyclic heterocycle, wherein if R^(B) is substituted then R^(B) issubstituted with 1-2 R¹² and 0-2 R¹³.
 33. The compound of any one ofclaims 1-32, or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof,wherein: R^(B) is an unsubstituted or substituted monocyclic carbocycle,or unsubstituted or substituted bicyclic carbocycle, wherein if R^(B) issubstituted then R^(B) is substituted with 1-2 R¹² and 0-2 R¹³.
 34. Thecompound of any one of claims 1-33, or a pharmaceutically acceptablesalt, solvate, diastereomeric mixture, individual enantiomers or prodrugthereof, wherein: R^(B) is an unsubstituted or substituted monocycliccarbocycle selected from unsubstituted or substituted phenyl,unsubstituted or substituted cyclopropyl, unsubstituted or substitutedcyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted orsubstituted cyclopentenyl, unsubstituted or substituted cyclohexyl, orunsubstituted or substituted cyclohexenyl, wherein if R^(B) issubstituted then R^(B) is substituted with 1-2 R¹² and 0-2 R¹³.
 35. Thecompound of any one of claims 1-34, or a pharmaceutically acceptablesalt, solvate, diastereomeric mixture, individual enantiomers or prodrugthereof, wherein: R^(B) is an unsubstituted or substituted phenyl,wherein if R^(B) is substituted then R^(B) is substituted with 1-2 R¹²and 0-2 R¹³.
 36. The compound of any one of claims 1-35, or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: R^(B) is

t is 0, 1, or
 2. 37. The compound of any one of claims 1-36, or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: R^(B) is


38. The compound of any one of claims 1-32, or a pharmaceuticallyacceptable salt, solvate, diastereomeric mixture, individual enantiomersor prodrug thereof, wherein: R^(B) is an unsubstituted or substitutedbicyclic carbocycle selected from unsubstituted or substituted naphthyl,unsubstituted or substituted indanyl, unsubstituted or substitutedindenyl, or unsubstituted or substituted tetrahyodronaphthyl, wherein ifR^(B) is substituted then R^(B) is substituted with 1-2 R¹² and 0-2 R¹³.39. The compound of any one of claims 1-32, or a pharmaceuticallyacceptable salt, solvate, diastereomeric mixture, individual enantiomersor prodrug thereof, wherein: R^(B) is an unsubstituted or substitutedmonocyclic heterocycle containing 1-4 N atoms and 0 or 1 or S atom,unsubstituted or substituted monocyclic heterocycle containing 0-4 Natoms and 1 O or S atoms, unsubstituted or substituted bicyclicheterocycle containing 1-4 N atoms and 0 or 1 O or S atoms, orunsubstituted or substituted bicyclic heterocycle containing 0-4 N atomsand 1 O or S atoms, wherein if R^(B) is substituted then R^(B) issubstituted with 1-2 R¹² and 0-2 R¹³.
 40. The compound of claim 39, or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: R^(B) is anunsubstituted or substituted monocyclic heterocycle selected fromunsubstituted or substituted furanyl, unsubstituted or substitutedpyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted orsubstituted thiazolyl, unsubstituted or substituted imidazolyl,unsubstituted or substituted pyrazolyl, unsubstituted or substitutedtriazolyl, unsubstituted or substituted tetrazolyl, unsubstituted orsubstituted isoxazolyl, unsubstituted or substituted isothiazolyl,unsubstituted or substituted oxadiazolyl, unsubstituted or substitutedthiadiazolyl, unsubstituted or substituted pyridinyl, unsubstituted orsubstituted pyrimidinyl, unsubstituted or substituted pyrazinyl,unsubstituted or substituted pyridazinyl, and unsubstituted orsubstituted triazinyl, wherein if R^(B) is substituted then R^(B) issubstituted with 1-2 R¹² and 0-2 R¹³.
 41. The compound of claim 39, or apharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: R^(B) is anunsubstituted or substituted unsubstituted or substituted pyridinyl,unsubstituted or substituted pyrimidinyl, unsubstituted or substitutedpyrazinyl, or unsubstituted or substituted pyridazinyl, wherein if R^(B)is substituted then R^(B) is substituted with R¹² and 0-1 R¹³, whereinR¹² and R¹³ are in a ortho-, meta-, or para-relationship on R^(B). 42.The compound of claim 39, or a pharmaceutically acceptable salt,solvate, diastereomeric mixture, individual enantiomers or prodrugthereof, wherein: R^(B) is an unsubstituted or substituted bicyclicheterocycle selected from unsubstituted or substituted quinolinyl,unsubstituted or substituted isoquinolinyl, unsubstituted or substitutedquinazolinyl, unsubstituted or substituted quinoxalinyl, unsubstitutedor substituted naphthyridinyl, unsubstituted or substituted indolyl,unsubstituted or substituted indazolyl, unsubstituted or substitutedbenzoxazolyl, unsubstituted or substituted benzisoxazolyl, unsubstitutedor substituted benzofuranyl, unsubstituted or substituted benzothienyl,unsubstituted or substituted benzothiazolyl, unsubstituted orsubstituted benzimidazolyl, unsubstituted or substituted purinyl,unsubstituted or substituted cinnolinyl, unsubstituted or substitutedphthalazinyl, unsubstituted or substituted pteridinyl, unsubstituted orsubstituted pyridopyrimidinyl, unsubstituted or substitutedpyrazolopyrimidinyl, unsubstituted or substituted azaindolyl,unsubstituted or substituted indolinyl, unsubstituted or substitutedisoindolinyl, unsubstituted or substituted indolinonyl, unsubstituted orsubstituted isoindolinonyl, or unsubstituted or substitutedquinolinonyl, wherein if R^(B) is substituted then R^(B) is substitutedwith 1-2 R¹² and 0-2 R¹³.
 43. The compound of any one of claims 1-42, ora pharmaceutically acceptable salt, solvate, diastereomeric mixture,individual enantiomers or prodrug thereof, wherein: each R¹² isindependently hydrogen, halogen, unsubstituted or substitutedC₁-C₄alkyl, unsubstituted or substituted C₁-C₄alkoxy, unsubstituted orsubstituted C₁-C₄fluoroalkyl, unsubstituted or substitutedC₁-C₄fluoroalkoxy, unsubstituted or substituted monocyclic carbocycle,unsubstituted or substituted monocyclic heterocycle, —CN, —OH, —CO₂R¹⁴,—CH₂CO₂R¹⁴, —C(═O)NR¹⁴R¹⁵, —CH₂C(═O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —CH₂NR¹⁴R¹⁵,—NR¹⁴C(═O)R¹⁵, —CH₂NR¹⁴C(═O)R¹⁵, —SR¹⁴, —S(═O)R¹⁵, —SO₂R¹⁵, or—SO₂NR¹⁴R¹⁵, wherein if R¹² is substituted then R¹² is substituted withR¹⁶; each R¹³ is independently hydrogen, halogen, unsubstituted orsubstituted C₁-C₄alkyl, unsubstituted or substituted C₁-C₄alkoxy,unsubstituted or substituted C₁-C₄fluoroalkyl, unsubstituted orsubstituted C₁-C₄fluoroalkoxy, unsubstituted or substituted monocycliccarbocycle, unsubstituted or substituted monocyclic heterocycle, —CN,—OH, wherein if R¹³ is substituted then R¹³ is substituted with R¹⁶. 44.The compound of any one of claims 1-43, or a pharmaceutically acceptablesalt, solvate, diastereomeric mixture, individual enantiomers or prodrugthereof, wherein: R⁴ is hydrogen, or unsubstituted or substituted C₁-C₆alkyl, wherein if R⁴ is substituted then it is substituted with 1-4 R¹⁶;R⁵ is hydrogen, or unsubstituted or substituted C₁-C₆ alkyl, wherein ifR⁵ is substituted then it is substituted with 1-4 R¹⁶; R⁷ is hydrogen;or R⁴ and R⁵ are taken together with the nitrogen atom to which they areattached to form a monocyclic 4- to 7-membered heterocyclic ring,wherein if the heterocyclic ring is substituted then the heterocyclicring is substituted with 1-4 R¹⁶; or R⁴ and R⁷ are taken together withthe nitrogen atom to which they are attached to form a monocyclic 4- to7-membered heterocyclic ring, wherein if the heterocyclic ring issubstituted then the heterocyclic ring is substituted with 1-4 R¹⁶. 45.The compound of any one of claims 1-44, or a pharmaceutically acceptablesalt, solvate, diastereomeric mixture, individual enantiomers or prodrugthereof, wherein: R⁴ is hydrogen, methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, sec-butyl, or tert-butyl; R⁵ is hydrogen, methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or tert-butyl;R⁷ is hydrogen; or R⁴ and R⁵ are taken together with the nitrogen atomto which they are attached to form an unsubstituted or substitutedmonocyclic 4- to 7-membered heterocyclic ring selected fromunsubstituted or substituted azetidinyl, unsubstituted or substitutedpyrrolidinyl, unsubstituted or substituted pyrrolidinonyl, unsubstitutedor substituted piperidinyl, unsubstituted or substituted morpholinyl,unsubstituted or substituted thiomorpholinyl, unsubstituted orsubstituted piperazinyl, or unsubstituted or substituted azepanyl,wherein if the heterocyclic ring is substituted then the heterocyclicring is substituted with 1-4 R¹⁶; or R⁴ and R⁷ are taken together withthe nitrogen atom to which they are attached to form an unsubstituted orsubstituted monocyclic 4- to 7-membered heterocyclic ring selected fromunsubstituted or substituted azetidinyl, unsubstituted or substitutedpyrrolidinyl, unsubstituted or substituted pyrrolidinonyl, unsubstitutedor substituted piperidinyl, unsubstituted or substituted morpholinyl,unsubstituted or substituted thiomorpholinyl, unsubstituted orsubstituted piperazinyl, or unsubstituted or substituted azepanyl,wherein if the heterocyclic ring is substituted then the heterocyclicring is substituted with 1-4 R¹⁶.
 46. The compound of any one of claims11-45, or a pharmaceutically acceptable salt, solvate, diastereomericmixture, individual enantiomers or prodrug thereof, wherein:


47. The compound of any one of claims 1-46, or a pharmaceuticallyacceptable salt, solvate, diastereomeric mixture, individual enantiomersor prodrug thereof, wherein: R⁴ is hydrogen, methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, sec-butyl, or tert-butyl; R⁵ is hydrogen,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, ortert-butyl; and R⁷ is hydrogen.
 48. The compound of any one of claims11-44, or a pharmaceutically acceptable salt, solvate, diastereomericmixture, individual enantiomers or prodrug thereof, wherein:

p is 1, 2, or 3; and q is 0, 1, or
 2. 49. The compound of any one ofclaims 11-44, or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof,wherein:

p is 1, 2, or 3; and q is 0, 1, or
 2. 50. The compound of any one ofclaims 1-49, or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof,wherein: R⁹ is hydrogen, unsubstituted or substituted C₁-C₆ alkyl, orunsubstituted or substituted benzyl, wherein if R⁹ is substituted thenR⁹ is substituted with 1-4 R¹⁶.
 51. The compound of any one of claims1-50, or a pharmaceutically acceptable salt, solvate, diastereomericmixture, individual enantiomers or prodrug thereof, wherein: R⁹ ismethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl,tert-butyl, or benzyl.
 52. A compound that is: 1-1:3-(3-chloro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-2:N-[(2S)-2-aminopropyl]-3-(3-chloro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methylquinoline-4-carboxamide;1-3:N-[(2S)-2-aminobutyl]-3-(3-chloro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methylquinoline-4-carboxamide;1-4:3-(3-fluoro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-5:3-(3-chloro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2R)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-6:3-(3-fluoro-5-methoxyphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-7:N-[(2S)-azetidin-2-ylmethyl]-3-(3-fluoro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methylquinoline-4-carboxamide;1-8:N-[(2S)-2-aminobutyl]-6-(3-carbamoyl-5-hydroxyphenyl)-3-(3-chloro-5-methylphenyl)-N-methylquinoline-4-carboxamide;1-9:N-[(2S)-2-aminobutyl]-6-(3-cyano-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;1-10:N-[(2S)-2-aminobutyl]-6-(3-cyano-5-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;1-11:N-[(2S)-2-aminobutyl]-3-(3-fluoro-5-methylphenyl)-6-(5-hydroxy-2-methylphenyl)-N-methylquinoline-4-carboxamide;1-12:N-[(2S)-2-aminobutyl]-6-(3-cyano-2-methylphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;1-13:N-[(2S)-2-aminobutyl]-6-(3-fluoro-2-methylphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;1-14:N-[(2S)-2-aminobutyl]-6-(5-cyano-2-methylphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;1-15:N-[(2S)-2-aminobutyl]-6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;1-16:6-(3-cyanophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-17:N-[(2S)-2-aminobutyl]-6-(3-fluoro-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;1-18:3-(3-fluorophenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-19:N-[(2S)-2-aminopropyl]-6-(3-cyano-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;1-20:N-[(2S)-2-aminopropyl]-6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;1-21:6-(3-cyano-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-22:6-(3-cyano-5-fluorophenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-23:3-(3,5-difluorophenyl)-6-(2-fluoro-3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-24:6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-25:6-(3-cyano-2-fluorophenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-26:6-(3-carbamoyl-5-fluorophenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-27:6-(5-cyano-2-methoxyphenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-28:6-(5-cyano-2-fluorophenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-29:3-(3-fluoro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-(morpholin-3-ylmethyl)quinoline-4-carboxamide;1-30:6-(3-cyano-5-methoxyphenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-31:6-(2-chloro-3-hydroxyphenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-32:N-[(2S)-2-aminobutyl]-6-(3-cyano-5-methoxyphenyl)-3-(3,5-difluorophenyl)-N-methylquinoline-4-carboxamide;1-33:6-(3-carbamoyl-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-34:6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-35:6-(3-cyano-5-fluorophenyl)-3-[3-fluoro-5-(2-hydroxyethyl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-36:3-fluoro-5-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]benzoicacid; 1-37:4-{3-[6-(3-cyano-5-fluorophenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-3-yl]-5-fluorophenoxy}butanoicacid; 1-38:N-[(2S)-2-aminobutyl]-6-(3-cyano-5-hydroxyphenyl)-3-(3,5-difluorophenyl)-N-methylquinoline-4-carboxamide;1-39:6-(3-cyano-5-fluorophenyl)-3-[3-fluoro-5-(2-hydroxyethoxy)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-40:6-[3-cyano-5-(trifluoromethyl)phenyl]-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-41:6-(2-chloro-3-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-42:6-(3-cyano-5-fluorophenyl)-3-[3-fluoro-5-(2-methoxyethoxy)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-43:3-(3-fluoro-5-methylphenyl)-6-[3-hydroxy-2-(methoxymethyl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide1-44:3-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]benzoicacid; 1-45:6-(3-cyano-2-methylphenyl)-3-[3-fluoro-5-(2-hydroxyethyl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-46:4-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]benzoicacid; 1-47:2-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]benzoicacid; 1-48:2-{3-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]phenyl}aceticacid; 1-49: methyl2-{3-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]phenyl}acetate;1-50:3-{3-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]phenyl}propanoicacid; 1-51:6-(3-cyano-2-methylphenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-52:6-(5-cyano-2-methylphenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-53:6-(3-carbamoyl-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-54:6-(3-carbamoyl-4-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-55:N-[(2S)-2-aminobutyl]-6-(3-cyano-5-fluorophenyl)-3-(3,5-difluorophenyl)-N-methylquinoline-4-carboxamide;1-56:6-(3-cyano-5-fluorophenyl)-3-(2,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-57:3-(2-chloro-5-methylphenyl)-6-(3-cyano-5-fluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-58:6-(3-cyano-5-fluorophenyl)-3-(5-fluoro-2-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-59:2-{3-fluoro-5-[3-(3-fluoro-5-methylphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-6-yl]phenyl}aceticacid; 1-60:3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-6-(3-sulfamoylphenyl)quinoline-4-carboxamide;1-61:6-(3,5-difluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(3S)-pyrrolidin-3-yl]quinoline-4-carboxamide;1-62:6-(3,5-difluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-63:6-(6-carbamoylpyrazin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-64:6-(2-chloro-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-65:2-{3-chloro-5-[6-(3-cyano-5-fluorophenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}quinolin-3-yl]phenoxy}aceticacid; 1-66:3-(3-fluoro-5-methylphenyl)-6-(3-fluoro-5-sulfamoylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-67:6-(3-cyano-5-fluorophenyl)-3-(2,3-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-68:N-[(2S)-2-amino-3-methylbutyl]-6-(3,5-difluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;1-69:6-(3-cyano-5-fluorophenyl)-3-[3-fluoro-5-(2-hydroxypropan-2-yl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-70:N-[(2S)-2-aminobutyl]-6-[3-fluoro-5-(trifluoromethyl)phenyl]-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;1-71:6-(3-cyano-5-fluorophenyl)-3-[3-fluoro-5-(prop-1-en-2-yl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-72:6-(3-carbamoyl-4-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-73:3-[3-(dimethylcarbamoyl)phenyl]-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-74:6-[3-(carbamoylmethyl)-5-fluorophenyl]-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-75:N-[(2S)-2-aminopropyl]-6-(3-carbamoyl-5-methoxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;1-76:3-(4-{[(2S)-2-aminopropyl](methyl)carbamoyl}-3-(3-fluoro-5-methylphenyl)quinolin-6-yl)-5-methoxybenzoicacid; 1-76:6-[3-cyano-5-(methylcarbamoyl)phenyl]-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-77:6-(3-cyano-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-78:6-(3-carbamoyl-5-cyanophenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-79:6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-{[(2S,4R)-4-fluoropyrrolidin-2-yl]methyl}-N-methylquinoline-4-carboxamide;1-80:N-[(2S)-azetidin-2-ylmethyl]-3-(3-chloro-5-methylphenyl)-6-(3-cyano-5-fluorophenyl)-N-methylquinoline-4-carboxamide;1-81:N-[(2S)-azetidin-2-ylmethyl]-6-(3-carbamoyl-5-fluorophenyl)-3-(3-chloro-5-methylphenyl)-N-methylquinoline-4-carboxamide;1-82:N-[(2S)-azetidin-2-ylmethyl]-6-(3-cyano-5-fluorophenyl)-3-(3,5-dichlorophenyl)-N-methylquinoline-4-carboxamide;1-83:N-[(2S)-azetidin-2-ylmethyl]-6-(3-carbamoyl-5-fluorophenyl)-3-(3,5-dichlorophenyl)-N-methylquinoline-4-carboxamide;1-84:N-[(2S)-azetidin-2-ylmethyl]-3-(3-chloro-5-methylphenyl)-6-(3-cyano-2-hydroxyphenyl)-N-methylquinoline-4-carboxamide;1-85:N-[(2S)-azetidin-2-ylmethyl]-6-(3-cyano-2-hydroxyphenyl)-3-(3,5-dichlorophenyl)-N-ethylquinoline-4-carboxamide;1-86:N-[(2S)-azetidin-2-ylmethyl]-3-(3-chloro-5-fluorophenyl)-6-(3-cyano-2-hydroxyphenyl)-N-methylquinoline-4-carboxamide;1-87:3-(3-chloro-5-fluorophenyl)-6-(3-cyano-2-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-88:6-(3-carbamoyl-5-methylphenyl)-3-(3-chloro-5-fluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;1-89:N-[(2S)-2-amino-4-fluorobutyl]-6-(3,5-difluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;1-90:6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-{[(2S,4S)-4-fluoropyrrolidin-2-yl]methyl}-N-methylquinoline-4-carboxamide;1-91:6-(3-fluoro-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;2-1:3-(3-chloro-5-methylphenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;2-2:3,6-bis(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;2-3:3-(3-chloro-5-methylphenyl)-6-(2-fluoro-5-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;2-4:3-(3-chloro-5-methylphenyl)-6-(3-cyano-5-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;2-5:N-[(2S)-2-aminobutyl]-6-(3-cyano-5-hydroxyphenyl)-3-(3,5-dimethylphenyl)-N-methyl-1,5-naphthyridine-4-carboxamide;2-6:N-[(2S)-2-aminobutyl]-3-(3-chloro-5-methylphenyl)-6-(3-cyano-5-hydroxyphenyl)-N-methyl-1,5-naphthyridine-4-carboxamide;2-7:N-[(2S)-2-aminobutyl]-6-(3-cyano-5-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-1,5-naphthyridine-4-carboxamide;2-8:6-(3-hydroxyphenyl)-N-methyl-3-[3-(1H-pyrazol-1-yl)phenyl]-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;2-9:3-(3,5-difluorophenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;2-10:6-(3-cyano-5-fluorophenyl)-3-[3-(2-hydroxyethyl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;2-11:6-(3-cyano-5-fluorophenyl)-N-methyl-3-phenyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;2-12:6-(3-cyano-5-fluorophenyl)-3-(3-methoxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;2-13:6-(3-cyano-5-fluorophenyl)-3-(3-fluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;2-14:6-(3-cyano-5-fluorophenyl)-3-[3-(acetamidomethyl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;2-15:6-(3-cyano-5-fluorophenyl)-3-(3-cyanophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;2-16:6-(3-cyano-5-fluorophenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;2-17:6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;2-18:6-(3-cyano-5-fluorophenyl)-3-(3-fluoro-5-methoxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;2-19:6-(3-cyanophenyl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;2-20:2-{3-[6-(3-hydroxyphenyl)-4-[methyl(pyrrolidin-2-ylmethyl)carbamoyl]-1,5-naphthyridin-3-yl]phenyl}aceticacid; 2-21: methyl2-{3-[6-(3-hydroxyphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}-1,5-naphthyridin-3-yl]phenyl}acetate;2-22:3-{3-[6-(3-hydroxyphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}-1,5-naphthyridin-3-yl]phenyl}propanoicacid; 2-23: methyl3-{3-[6-(3-hydroxyphenyl)-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]carbamoyl}-1,5-naphthyridin-3-yl]phenyl}propanoate;2-24:6-(3-carbamoyl-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-1:6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-2:3-(3-fluoro-5-methylphenyl)-N-methyl-6-(pyrrolidin-1-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-3:3-(3-fluoro-5-methylphenyl)-6-(3-hydroxypiperidin-1-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-4:6-(3-hydroxyphenyl)-N-methyl-3-(pyrrolidin-1-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-5:6-(3-hydroxyphenyl)-N-methyl-3-(6-methylpyridin-2-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-6:3-(2,6-dimethylmorpholin-4-yl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-7:6-(3-cyano-5-fluorophenyl)-N-methyl-3-(prop-1-yn-1-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-8:6-(5-cyanopyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-9:6-(3-cyano-5-fluorophenyl)-3-(cyclopent-1-en-1-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-10:3-(3-fluoro-5-methylphenyl)-N-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-11:6-(3-hydroxyphenyl)-N-methyl-3-(piperidin-1-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-12:6-(3-hydroxyphenyl)-N-methyl-3-(morpholin-4-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-13:6-(6-cyanopyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-14:6-(4-cyanopyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-15:6-(2-amino-5-cyanopyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-16:6-(2-cyanopyridin-4-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-17:3-[3-(hydroxymethyl)pyrrolidin-1-yl]-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-18:6-(3-hydroxyphenyl)-N-methyl-3-(prop-1-yn-1-yl)-N-((2S)-pyrrolidin-2-ylmethyl)-1,5-naphthyridine-4-carboxamide;3-19:6-(4-cyanopyrimidin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-20:3-(cis-2,6-dimethylmorpholin-4-yl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-21:3-(trans-2,6-dimethylmorpholin-4-yl)-6-(3-hydroxyphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-22:6-(5-cyano-2,4-dimethylpyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-33:6-(2-carbamoylpyridin-4-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-34:6-(3-cyano-5-fluorophenyl)-3-(2-fluoro-3,5-dimethylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-35:6-(3-cyano-5-fluorophenyl)-3-(2,6-dimethylmorpholin-4-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-36:6-(3-cyano-5-fluorophenyl)-3-(2,6-dimethylmorpholin-4-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-37:6-[5-cyano-2-(methylamino)pyridin-3-yl]-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-38:6-[5-cyano-2-(dimethylamino)pyridin-3-yl]-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-39:6-(5-cyano-2-methylpyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-40:6-(5-cyanopyridin-3-yl)-3-[3-fluoro-5-(2-hydroxyethyl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-41:N-[(2S)-2-aminobutyl]-6-[5-cyano-2-(dimethylamino)pyridin-3-yl]-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;3-42:6-(3-cyano-5-fluorophenyl)-N-methyl-3-[(2R)-2-phenylmorpholin-4-yl]-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-43:6-(3-cyano-5-fluorophenyl)-N-methyl-3-(3-methylbutyl)-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-44:6-(6-carbamoylpyrazin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-45:6-(3-cyano-5-fluorophenyl)-3-(2,6-dimethylmorpholin-4-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-46:3-(3-fluoro-5-methylphenyl)-N-methyl-6-[6-(methylcarbamoyl)pyridin-2-yl]-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-47:6-(3-cyano-5-fluorophenyl)-N-methyl-3-[(2S)-2-phenylmorpholin-4-yl]-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-48:3-(3-fluoro-5-methylphenyl)-N-methyl-6-(pyridin-3-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-49:6-(3-cyano-5-fluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-3-(2,2,6,6-tetramethylmorpholin-4-yl)-1,5-naphthyridine-4-carboxamide;3-50:6-(3-carbamoyl-4,5-difluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-51:6-(6-aminopyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-52:6-(3-carbamoyl-2,5-difluorophenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-53:3-(3-fluoro-5-methylphenyl)-6-(6-methoxypyridin-2-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-54:6-(3-cyano-5-fluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-3-[5-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]-1,5-naphthyridine-4-carboxamide;3-55:6-(3-cyano-5-fluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-3-[5-(trifluoromethyl)-2,3-dihydro-1H-isoindol-2-yl]-1,5-naphthyridine-4-carboxamide;3-56:6-(5-cyano-2-hydroxypyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-57:6-(6-carbamoyl-3-methylpyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-58:6-(5-carbamoylpyridin-3-yl)-3-[3-fluoro-5-(2-hydroxyethyl)phenyl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-59:3-(3-fluoro-5-methylphenyl)-6-(5-fluoropyridin-3-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-60:3-(3-fluoro-5-methylphenyl)-6-(1H-indol-6-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-61:3-(3-fluoro-5-methylphenyl)-6-(1H-indol-4-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-62:6-(2-amino-5-fluoropyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-64:6-(3-carbamoyl-5-fluorophenyl)-3-[(cis)-2,6-dimethylmorpholin-4-yl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-65:3-(3-fluoro-5-methylphenyl)-N-methyl-6-(4-methylpyridin-3-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-66:3-(3-fluoro-5-methylphenyl)-N-methyl-6-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-67:N-[(2S)-2-aminobutyl]-6-(6-carbamoylpyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;3-68:6-(5-chloropyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-69:3-{3-azabicyclo[3.1.0]hexan-3-yl}-6-(3-cyano-5-fluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-70:6-(3-cyano-5-fluorophenyl)-N-methyl-3-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-71:3-(3-fluoro-5-methylphenyl)-N-methyl-6-(pyrimidin-5-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-72:6-[4-cyano-6-(morpholin-4-yl)pyridin-2-yl]-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-73:3-(3-fluoro-5-methylphenyl)-N-methyl-6-[2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-1,3-benzodiazol-4-yl]-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-74:3-(3-fluoro-5-methylphenyl)-6-(4-fluoropyridin-3-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-75:6-(4-chloropyridin-3-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-76:6-(3-cyano-5-fluorophenyl)-3-(3,3-difluoropyrrolidin-1-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-1,5-naphthyridine-4-carboxamide;3-77:6-(6-carbamoylpyridin-2-yl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-78:6-(6-carbamoyl-3-fluoropyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-79:6-(6-carbamoyl-3-methylpyridin-2-yl)-3-(3,5-difluorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-80:6-(4-carbamoylpyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-81:3-(3-fluoro-5-methylphenyl)-6-(5-methoxypyridin-3-yl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-82:3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-6-(6-sulfamoylpyridin-2-yl)quinoline-4-carboxamide;3-83:3-(3-fluoro-5-methylphenyl)-N-methyl-6-(5-methylpyridin-3-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-84:3-(3-fluoro-5-methylphenyl)-6-[5-(hydroxymethyl)pyridin-3-yl]-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-85:3-(3-chloro-5-methylphenyl)-6-(5-hydroxypyridin-3-yl)-N,7-dimethyl-N-[(2S)-pyrrolidin-2-ylmethyl]-3,4-dihydroquinazoline-4-carboxamide;3-86:6-[5-(difluoromethoxy)pyridin-3-yl]-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-87: ethyl(2S)-2-({1-[6-(6-carbamoylpyridin-2-yl)-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]-N-methylformamido}methyl)pyrrolidine-1-carboxylate;3-88:6-(6-carbamoylpyridin-2-yl)-3-(3-chloro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-89:6-(6-carbamoyl-3-fluoropyridin-2-yl)-3-(3-chloro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-90:6-(6-carbamoyl-3-methylpyridin-2-yl)-3-(3-chloro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-91:6-(6-carbamoyl-3-chloropyridin-2-yl)-3-(3-chloro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-92:N-[(2S)-azetidin-2-ylmethyl]-6-(6-carbamoylpyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;3-93:N-[(2S)-azetidin-2-ylmethyl]-6-(6-carbamoyl-3-fluoropyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;3-94:N-[(2S)-azetidin-2-ylmethyl]-6-(6-carbamoyl-3-methylpyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;3-95:N-[(2S)-azetidin-2-ylmethyl]-6-(6-carbamoyl-3-chloropyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methylquinoline-4-carboxamide;3-96:6-(6-carbamoylpyridin-2-yl)-3-(3,5-dichlorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-97:6-(6-carbamoyl-3-fluoropyridin-2-yl)-3-(3,5-dichlorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-98:6-(6-carbamoyl-3-methylpyridin-2-yl)-3-(3,5-dichlorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-99:6-(6-carbamoyl-3-chloropyridin-2-yl)-3-(3,5-dichlorophenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-100:N-[(2S)-azetidin-2-ylmethyl]-6-(6-carbamoylpyridin-2-yl)-3-(3,5-dichlorophenyl)-N-methylquinoline-4-carboxamide;3-101:N-[(2S)-azetidin-2-ylmethyl]-6-(6-carbamoyl-3-fluoropyridin-2-yl)-3-(3,5-dichlorophenyl)-N-methylquinoline-4-carboxamide;3-102:N-[(2S)-azetidin-2-ylmethyl]-6-(6-carbamoyl-3-methylpyridin-2-yl)-3-(3,5-dichlorophenyl)-N-methylquinoline-4-carboxamide;3-103:N-[(2S)-azetidin-2-ylmethyl]-6-(6-carbamoyl-3-chloropyridin-2-yl)-3-(3,5-dichlorophenyl)-N-methylquinoline-4-carboxamide;3-104:6-(6-carbamoylpyridin-2-yl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-{[(2S)-1-methylpyrrolidin-2-yl]methyl}quinoline-4-carboxamide;3-105:3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]-6-[5-(trifluoromethyl)pyridin-3-yl]quinoline-4-carboxamide;3-106:3-(3-fluoro-5-methylphenyl)-N-methyl-6-(4-oxo-3,4-dihydro-2H-1,3-benzoxazin-6-yl)-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;3-107:6-(3,5-difluoro-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)-N-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]quinoline-4-carboxamide;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, diastereomeric mixture, individual enantiomers or prodrugthereof.
 53. A pharmaceutical composition comprising a compound of anyone of claims 1-52, or a pharmaceutically acceptable salt, solvate,diastereomeric mixture, individual enantiomers or prodrug thereof, andat least one pharmaceutically acceptable excipient.
 54. Thepharmaceutical composition of claim 53, wherein the pharmaceuticalcomposition is formulated for administration to a mammal by intravenousadministration, subcutaneous administration, oral administration,inhalation, nasal administration, dermal administration, or ophthalmicadministration.
 55. The pharmaceutical composition of claim 53, whereinthe pharmaceutical composition is in the form of a tablet, a pill, acapsule, a liquid, a suspension, a gel, a dispersion, a solution, anemulsion, an ointment, or a lotion.
 56. A method of treating a diseaseor condition in a mammal that would benefit from the modulation of thesomatostatin receptor subtype 2 (SSTR2) activity comprisingadministering a compound as described in any one of claims 1-52, or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,diastereomeric mixture, individual enantiomers or prodrug thereof, tothe mammal in need thereof.
 57. The method of claim 56, wherein thecompound as described in any one of claims 1-52, or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, diastereomericmixture, individual enantiomers or prodrug thereof, is orallyadministered.
 58. The method of claim 56 or claim 57, wherein thedisease or condition is acromegaly, a neuroendocrine tumor, anophthalmic disease or condition, neuropathy, nephropathy, a respiratorydisease or condition, cancer, pain, a neurodegenerative disease orcondition, an inflammatory disease or condition, a psychiatric diseaseor condition, or combinations thereof.